Cannabinoid receptor modulators

ABSTRACT

Provided are certain methods useful in the treatment of pain comprising administering a compound of Formula Ia and pharmaceutical compositions thereof that modulate the activity of the cannabinoid CB 2  receptor;

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/001,131, filed Aug. 22, 2013, which application is a 35 USC 371National Stage Application of International Application No.PCT/US2012/026517, filed Feb. 24, 2012, which claims priority to U.S.Provisional Patent Application No. 61/446,729, filed Feb. 25, 2011, eachof which is hereby incorporated by reference in its entirety.

Cannabinoids are a group of extracellular signaling molecules that arefound in both plants and animals. Signals from these molecules aremediated in animals by two G-protein coupled receptors, CannnabinoidReceptor 1 (CB₁) and Cannabinoid Receptor 2 (CB₂). CB₁ is expressed mostabundantly in the neurons of the CNS but is also present at lowerconcentrations in a variety of peripheral tissues and cells (Matsuda, L.A. et al. (1990) Nature 346:561-564). In contrast, CB₂ is expressedpredominantly, although not exclusively, in non-neural tissues, e.g. inhematopoietic cells, endothelial cells, osteoblasts, osteoclasts, theendocrine pancreas, and cancerous cell lines (Munro, S. et al. (1993)Nature 365:61-65; and as reviewed in Pacher, P. et al. (2006) Pharmacol.Rev. 58(3): 389-462). As such, CB₁ is believed to be primarilyresponsible for mediating the psychotropic effects of cannabinoids onthe body, whereas CB₂ is believed to be primarily responsible for mostof their non-neural effects.

The texts of the references cited in this disclosure are hereinincorporated by reference in their entireties. In the event that adefinition of a term as incorporated by reference differs from themeaning defined herein, then the meaning provided herein is intended.

Provided is a composition comprising a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵, and R⁶ are each independently selected from:        H and C₁-C₆ alkyl;    -   X is NR⁷ and Y is CC(O)N(R⁸)R⁹; or    -   X is CC(O)N(R⁸)R⁹ and Y is NR⁷;    -   R⁷ is —R¹⁰—R¹¹—R¹²—R¹³; wherein:    -   R¹⁰ is selected from: C₁-C₆ alkylene, heteroarylene, and        heterocyclylene; or R¹⁰ is absent;    -   R¹¹ is selected from: —C(O)NH— and C₁-C₆ alkylene; or R¹¹ is        absent;    -   R¹² is C₁-C₆ alkylene; or R¹² is absent; and    -   R¹³ is selected from: C₁-C₆ alkyl, aryl, C₃-C₇ cycloalkyl,        heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆        alkyl, aryl, and heteroaryl are each optionally substituted with        one or two substituents selected from: C₁-C₆ alkoxy, C₁-C₆        alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, amino, C₃-C₇        cycloalkyl, cyano, C₂-C₈ dialkylamino, C₁-C₆ haloalkyl, halogen,        and hydroxyl;    -   R⁸ is —R¹⁴—R¹⁵—R¹⁶—R¹⁷; wherein:    -   R¹⁴ is selected from: C₁-C₆ alkylene, C₃-C₇ cycloalkenylene,        C₃-C₇ cycloalkylene, heteroarylene, and heterocyclylene; wherein        said C₁-C₆ alkylene and heterocyclylene are each optionally        substituted with one or more substituents selected from: C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, carboxy,        heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆ alkyl        and aryl are optionally substituted with one substituent        selected from: C₁-C₆ alkoxy, aryl, halogen, heteroaryl, and        hydroxyl; or R¹⁴ is absent;    -   R¹⁵ is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C₁-C₆ alkylene,        C₃-C₇ cycloalkylene, heteroarylene, and heterocyclylene; wherein        said heterocyclylene is optionally substituted with C₁-C₆ alkyl;        or R¹⁵ is absent;    -   R¹⁶ is C₁-C₆ alkylene; or R¹⁶ is absent; and    -   R¹⁷ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆        alkylamino, C₁-C₆ alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino,        aryl, arylamino, arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy,        carboxamide, carboxy, cyano, C₃-C₇ cycloalkyl, C₅-C₁₁        bicycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈ dialkylamino, C₂-C₈        dialkylsulfonamide, C₁-C₆ haloalkyl, heteroaryl, heteroaryloxy,        heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy;        wherein said C₁-C₆ alkylamino, amino, aryl, arylamino, aryloxy,        C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylamino,        heteroaryl, heterobicyclyl, heterocyclyl, and ureyl are each        optionally substituted with one or more substituents selected        from: C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆        alkylsulfonyl, amino, aryl, carboxy, cyano, C₃-C₇ cycloalkyl,        C₂-C₈ dialkylamino, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen,        heteroaryl, heterocyclyl, and hydroxyl; and    -   R⁹ is selected from H, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; or    -   R⁸ and R⁹ together with the nitrogen atom to which they are both        bonded form a group selected from: heterocyclyl and        heterobicyclyl, each optionally substituted with one or more        substituents selected from: Carbo-C₁-C₆-alkoxy, C₁-C₆ alkoxy,        C₁-C₆ alkyl, aryl, carbo-C₁-C₆-alkoxy, C₁-C₆ haloalkyl, halogen,        heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein        said aryl, C₁-C₆ alkyl, and heteroaryl are optionally        substituted with one substituent selected from: C₃-C₇        cycloalkyl, C₁-C₆ alkoxy, halogen, and hydroxyl,    -   and one or more known pharmaceutical agents selected from        analgesic agents and antidiabetic agents.

Also provided is a composition comprising a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof, one or more known pharmaceutical agents selected from analgesicagents and antidiabetic agents, and a pharmaceutically acceptablecarrier.

Also provided is a method for preparing a composition comprising thestep of admixing a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof, and one ormore known pharmaceutical agents selected from analgesic agents andantidiabetic agents.

Also provided is a method for preparing a composition comprising thestep of admixing a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof, one or moreknown pharmaceutical agents selected from analgesic agents andantidiabetic agents, and a pharmaceutically acceptable carrier.

Also provided is a composition obtained by any of the methods describedherein.

Also provided is a method for the treatment of pain in an individual inneed thereof, comprising administering to said individual, atherapeutically effective amount of a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof, and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents.

Also provided is a method for the treatment of pain in an individual inneed thereof, comprising prescribing to said individual, atherapeutically effective amount of a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof, and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents.

Also provided is a method for the management of pain in an individual inneed thereof, comprising administering to said individual, atherapeutically effective amount of a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof, and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents.

Also provided is a method for the management of pain in an individual inneed thereof, comprising prescribing to said individual, atherapeutically effective amount of a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof, and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents.

Also provided is a compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof, for use incombination with and one or more known pharmaceutical agents selectedfrom analgesic agents and antidiabetic agents.

Also provided is a compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof, for use in amethod for the treatment of pain in an individual in need thereof,comprising administering to said individual said compound and one ormore known pharmaceutical agents selected from analgesic agents,antidiabetic agents, osteoarthritis agents, and anticancer agents.

Also provided is a compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof, for use in amethod for the treatment of pain in an individual in need thereof,comprising prescribing to said individual said compound and one or moreknown pharmaceutical agents selected from analgesic agents, antidiabeticagents, osteoarthritis agents, and anticancer agents.

Also provided is a compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof, for use in amethod for the management of pain in an individual in need thereof,comprising administering to said individual said compound and one ormore known pharmaceutical agents selected from analgesic agents,antidiabetic agents, osteoarthritis agents, and anticancer agents.

Also provided is a compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof, for use in amethod for the management of pain in an individual in need thereof,comprising prescribing to said individual said compound and one or moreknown pharmaceutical agents selected from analgesic agents, antidiabeticagents, osteoarthritis agents, and anticancer agents.

Also provided is one or more known pharmaceutical agents selected fromanalgesic agents and antidiabetic agents for use in combination with acompound of Formula Ia, or a pharmaceutically acceptable salt, solvate,hydrate, and/or N-oxide thereof.

Also provided is one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents for use in a method for the treatment of pain in anindividual in need thereof, said method comprises administering to saidindividual one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents and a compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof.

Also provided is one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents for use in a method for the treatment of pain in anindividual in need thereof, said method comprises prescribing to saidindividual one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents and a compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof.

Also provided is one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents for use in a method for the management of pain in anindividual in need thereof, said method comprises administering to saidindividual one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents and a compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof.

Also provided is one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents for use in a method for the management of pain in anindividual in need thereof, said method comprises administering to saidindividual one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents and a compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof.

Also provided is a pharmaceutical product selected from: apharmaceutical composition, a formulation, a dosage form, a combinedpreparation, a twin pack, and a kit; comprising a compound of FormulaIa, or a pharmaceutically acceptable salt, solvate, hydrate, and/orN-oxide thereof, and one or more known pharmaceutical agents selectedfrom analgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents; for treating pain in an individual.

Also provided is a pharmaceutical product selected from: apharmaceutical composition, a formulation, a dosage form, a combinedpreparation, a twin pack, and a kit; comprising a compound of FormulaIa, or a pharmaceutically acceptable salt, solvate, hydrate, and/orN-oxide thereof, and one or more known pharmaceutical agents selectedfrom analgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents; for managing pain in an individual.

Also provided is the use of a compound of Formula Ia, or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof, and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents in the manufacture of a medicament for treating painin an individual.

Also provided is the use of a compound of Formula Ia, or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof, and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents in the manufacture of a medicament for managing painin an individual.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of Compound 493 in the FCA-induced hyperalgesiamodel of inflammatory pain in rats at 1 h post dosing. See Example 7.

FIG. 2 shows the effect of Compound 493 in the monosodium iodoacetate(MIA) model of osteoarthritis in rats at 1 h post dosing. See Example 5.

FIG. 3 shows the effect of 10 mg/kg of Compound 493 onpaclitaxel-induced allodynia in rats. See Example 8.

FIG. 4 shows the effect of Compound 493 on the skin incision model ofpostoperative pain in rats. See Example 6.

FIG. 5 shows a general synthesis of compounds described herein wherein Xis CC(O)N(R⁸)R⁹ and Y is NR⁷. First, a 2-(but-3-enyl)oxirane derivativeis cyclized by treatment with a base. The resulting bicyclic alcohol isoxidized to the ketone and reacted with a dialkyl oxalate derivative inthe presence of a base. The pyrazole ring is then formed by reactionwith a substituted hydrazine and the resulting ester is hydrolyzed andcoupled with an amine to form compounds described herein.

FIG. 6 shows a general synthesis of compounds described herein in whichR⁷ is a 4-oxy-pyrazin-2-yl group.

FIG. 7 shows a general synthesis of compounds described herein similarto the one shown in FIG. 5 except the group R⁷ is introduced subsequentto the formation of a tri-substituted pyrazole.

FIG. 8 shows a general synthesis of compounds described herein in whichR⁷ is either a 5-substituted-pyridin-2-yl group or a5-substituted-pyrazin-2-yl group.

FIG. 9 shows a general synthesis of compounds described herein in whichR⁷ is a 4-substituted-pyridin-2-yl group.

FIG. 10 shows a general synthesis of compounds described herein whereinX is NR⁷ and Y is CC(O)N(R⁸)R⁹. First, a bicyclo[3.1.0]hexan-3-olderivative is oxidized and the resulting ketone is reacted with adialkyl oxalate derivative in the presence of a base. The pyrazole ringis then formed by reaction with a substituted hydrazine and theresulting ester is hydrolyzed and coupled with an amine to formcompounds described herein.

FIG. 11 shows a differential scanning calorimetry (DSC) thermogram for asample containing a crystalline form of Compound 699 CH₂Cl₂ solvate anda thermogravimetric analysis (TGA) thermogram of a sample containing acrystalline form of Compound 699 CH₂Cl₂ solvate.

FIG. 12 shows an overlay of a powder X-ray diffraction pattern (PXRD)for a sample containing a crystalline form of Compound 699 CH₂Cl₂solvate obtained from recrystallization using CH₂Cl₂/hexane (Top Trace)and a powder X-ray diffraction pattern (PXRD) for a sample containing acrystalline form of Compound 699 CH₂Cl₂ solvate obtained by slurryingnon-solvated Compound 699 in CH₂Cl₂ (Bottom Trace). The PXRD showed thecrystalline solvate obtained from the CH₂Cl₂ slurry is substantiallyindistinguishable from the crystalline solvate resulting fromrecrystallized from CH₂Cl2/hexane.

FIG. 13 shows the effect of Compound 699 (10 mpk) compared to vehicle(methyl cellulose) in the STZ-induced PDPN Model. See Example 12.

FIG. 14 shows the effect of Compound 919 (10 mpk) compared to vehicle(methyl cellulose) in the STZ-induced PDPN Model. See Example 12.

FIG. 15 shows the effect of Compound 699 (1 mpk) and morphine (1 mpk) inrelieving osteoarthritis pain. See Example 13.

FIG. 16 shows a powder X-ray diffraction pattern (PXRD) for a samplecontaining an anhydrous crystalline form of Compound 699.

FIG. 17 shows a differential scanning calorimetry (DSC) thermogram for asample containing an anhydrous crystalline form of Compound 699 and athermogravimetric analysis (TGA) thermogram of a sample containing ananhydrous crystalline form of Compound 699.

FIG. 18 shows an adsorption and desorption isotherm, Dyanmic MoistureSorption (DMS), for a sample containing anhydrous crystalline form ofCompound 699.

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “acute pain” is intended to mean pain from a specific cause(such as injury, infection, inflammation, etc.) that has lasted for alimited period of time (as opposed to chronic pain).

The term “chronic pain” is intended to mean pain that persists or recursfor greater than about 3 months and/or persists for greater than 1 monthafter resolution of an acute tissue injury, or accompanies a nonhealinglesion. Causes include chronic disorders (eg, cancer, arthritis,diabetes) and injuries (eg, herniated disk, torn ligament), and manyprimary pain disorders (eg, neuropathic pain, fibromyalgia, chronicheadache).

The term “inflammatory pain” is intended to describe the subset of acuteand chronic pain that results from inflammatory processes, such as mayarise in the case of infections, arthritis and neoplasia or tumorrelated hypertrophy. Tumor or cancer associated pain is, therefore,considered to fall within the category of inflammatory pain. Examples ofconditions associated with inflammatory pain include rheumatoidarthritis, osteo-arthritis, psoriatic arthropathy, arthritis associatedwith other inflammatory and autoimmune conditions, degenerativeconditions such as back strain and mechanical back pain or disc disease,post operative pain, pain from an injury such as a soft tissue bruise orstrained ligament or broken bone, abscess or cellulitis, fibrositis ormyositis.

The term “analgesic agent” is intended to mean any biomolecule, drug oractive agent that alleviates or prevents pain.

The term “co-analgesic agent” is intended to mean a drug that typicallyaddresses indications other than pain relief, but possesses analgesicaction for certain painful conditions.

The term “agonist” is intended to mean a moiety that interacts with andactivates a G-protein-coupled receptor, for instance a cannabinoidreceptor, and can thereby initiate a physiological or pharmacologicalresponse characteristic of that receptor. For example, an agonist mayactivate an intracellular response upon binding to a receptor, orenhance GTP binding to a membrane.

The term “antagonist” is intended to mean a moiety that competitivelybinds to the receptor at the same site as an agonist (for example, theendogenous ligand), but which does not activate the intracellularresponse initiated by the active form of the receptor and can therebyinhibit the intracellular responses by an agonist or partial agonist. Anantagonist does not diminish the baseline intracellular response in theabsence of an agonist or partial agonist.

The term “hydrate” as used herein means a compound described herein or asalt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The term “solvate” as used herein means a compound described herein or asalt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. In some embodiments, the solvents are volatile,non-toxic, and/or acceptable for administration to humans in traceamounts.

The term “in need of treatment” and the term “in need thereof” whenreferring to treatment are used interchangeably to mean a judgment madeby a caregiver (e.g. physician, nurse, nurse practitioner, etc. in thecase of humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsdescribed herein. Accordingly, the compounds described herein can beused in a protective or preventive manner; or compounds described hereincan be used to alleviate, inhibit or ameliorate the disease, conditionor disorder.

The term “individual” is intended to mean any animal, including mammals,such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle,sheep, horses, or primates, and in some embodiments, humans.

The term “inverse agonist” is intended to mean a moiety that binds tothe endogenous form of the receptor or to the constitutively activatedform of the receptor and which inhibits the baseline intracellularresponse initiated by the active form of the receptor below the normalbase level of activity which is observed in the absence of an agonist orpartial agonist, or decreases GTP binding to a membrane. In someembodiments, the baseline intracellular response is inhibited in thepresence of the inverse agonist by at least 30%, such as by at least 50%and for example, by at least 75%, as compared with the baseline responsein the absence of the inverse agonist.

The term “modulate or modulating” is intended to mean an increase ordecrease in the amount, quality, response or effect of a particularactivity, function or molecule.

The term “pharmaceutical composition” is intended to mean a compositioncomprising at least one active ingredient; including but not limited to,salts, solvates, and hydrates of compounds described herein, whereby thecomposition is amenable to investigation for a specified, efficaciousoutcome in a mammal (for example, without limitation, a human). Those ofordinary skill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

The term “therapeutically effective amount” is intended to mean theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician or caregiver or by an individual, whichincludes one or more of the following:

(1) Preventing the disease, for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) Inhibiting the disease, for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and

(3) Ameliorating the disease, for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The term “C₁-C₄ acyl” is intended to mean a radical comprising a C₁-C₄alkyl group attached to the carbon of a carbonyl group, wherein C₁-C₄alkyl has the same definition as found herein. Examples include, but arenot limited to acetyl, propionyl, butyryl, isobutyryl, pivaloyl, and thelike.

The term “amino” is intended to mean the group —NH₂.

The term “aryl” is intended to mean a ring system containing 6 to 10carbon atoms, that may contain a single ring or two fused rings, andwherein at least one ring is aromatic. Examples include phenyl, indanyl,and naphthyl.

The term “arylamino” is intended to mean a radical comprising an arylgroup, attached to a nitrogen, wherein aryl has the same definition asfound herein. Examples include, but are not limited to, phenylamino andnaphthylamino.

The term “arylcarbonyl” is intended to mean a radical comprising an arylgroup, attached to the carbon atom of a carbonyl group, wherein aryl hasthe same definition as found herein. Examples include, but are notlimited to, benzoyl and naphthylcarbonyl.

The term “aryloxy” is intended to mean a radical comprising an arylgroup, attached to an oxygen, wherein aryl has the same definition asfound herein. Examples include, but are not limited to, phenoxy andnaphthyloxy.

The term “C₁-C₆ alkoxy” is intended to mean a radical comprising a C₁-C₆alkyl group attached directly to an oxygen atom, wherein C₁-C₆ alkyl hasthe same definition as found herein. Some embodiments contain 1 to 5carbons. Some embodiments contain 1 to 4 carbons. Some embodimentscontain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons.Examples include, but are not limited to methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, isobutoxy, s-butoxy, and the like.

The term “C₁-C₆ alkoxycarbonyl” is intended to mean a radical comprisinga single C₁-C₆ alkoxy group attached to the carbon of a carbonyl group,wherein C₁-C₆ alkoxy has the same definition as found herein. Thealkoxycarbonyl group may be represented by the following:

The term “C₁-C₆ alkyl” is intended to mean a straight or branched carbonradical containing 1 to 6 carbons. Some embodiments contain 1 to 5carbons. Some embodiments contain 1 to 4 carbons. Some embodimentscontain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons.Examples of an alkyl group include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, pentyl,isopentyl, t-pentyl, neopentyl, 1-methylbutyl [i.e., —CH(CH₃)CH₂CH₂CH₃],2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl, and the like.

The term “C₁-C₄ alkyl” is intended to mean a straight or branched carbonradical containing 1 to 4 carbons. Some embodiments contain 1 to 3carbons. Some embodiments contain 1 or 2 carbons. Examples of an alkylgroup include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, and the like.

The term “C₁-C₆ alkylamino” is intended to mean a radical comprising oneC₁-C₆ alkyl group attached to an NH group, wherein C₁-C₆ alkyl has thesame meaning as described herein.

Some examples include, but are not limited to, methylamino, ethylamino,n-propylamino, isopropylamino, n-butylamino, s-butylamino,isobutylamino, t-butylamino, and the like. Some embodiments are “C₁-C₂alkylamino.”

The term “C₁-C₆ alkylcarboxamide” is intended to mean a single C₁-C₆alkyl group attached to either the carbon or the nitrogen of an amidegroup, wherein C₁-C₆ alkyl has the same definition as found herein. TheC₁-C₆ alkylcarboxamido group may be represented by the following:

Examples include, but are not limited to, N-methylcarboxamide,N-ethylcarboxamide, N-n-propylcarboxamide, N-isopropylcarboxamide,N-n-butylcarboxamide, N-s-butylcarboxamide, N-isobutylcarboxamide,N-t-butylcarboxamide, and the like.

The term “C₁-C₆ alkylene” is intended to mean a straight or branched,saturated aliphatic, divalent radical having 1 to 6 carbon atoms. Someembodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4carbons. Some embodiments contain 1 to 3 carbons. Some embodimentscontain 1 or 2 carbons. Examples include, but are not limited to,methylene, ethylene, n-propylene, isopropylene, n-butylene, s-butylene,isobutylene, t-butylene, pentylene, isopentylene, t-pentylene,neopentylene, 1-methylbutylene [i.e., —CH(CH₃)CH₂CH₂CH₃],2-methylbutylene [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexylene, and the like.

The term “C₁-C₆ alkylsulfonyl” is intended to mean a radical comprisinga C₁-C₆ alkyl group attached to the sulfur of a sulfonyl group, whereinthe C₁-C₆ alkyl radical has the same definition as described herein.Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, s-butylsulfonyl,isobutylsulfonyl, t-butylsulfonyl, and the like.

The term “C₅-C₁₁ bicycloalkyl” is intended to mean a radical comprisingtwo fused or bridged, saturated rings containing 5 to 11 ring carbonatoms. Examples of a bicycloalkyl group include, but are not limited to,bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, and the like.

The term “C₃-C₇ cycloalkenylene” is intended to mean is intended to meana mono unsaturated ring di-radical containing 3 to 7 carbons. Someembodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5carbons. Some embodiments contain 5 to 7 carbons. Some embodimentscontain 3 to 4 carbons. Examples include cyclopropenediyl,cyclobutenediyl, cyclopentenediyl, cyclohexenediyl, cycloheptenediyl,and the like.

The term “C₃-C₇ cycloalkyl” is intended to mean a saturated ring radicalcontaining 3 to 7 carbons. Some embodiments contain 3 to 6 carbons. Someembodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7carbons. Some embodiments contain 3 to 4 carbons. Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike.

The term “C₃-C₇ cycloalkylamino” is intended to mean a radicalcomprising a C₃-C₇ cycloalkyl attached the nitrogen of an amino group,wherein C₃-C₇ cycloalkyl has the same definition as found herein.Examples include, but are not limited to, cyclopropylamino,cyclobutylamino, cyclopentylamino, cyclohexylamino, and the like.

The term “C₃-C₇ cycloalkylene” is intended to mean a saturated ringdi-radical containing 3 to 7 carbons. Some embodiments contain 3 to 6carbons. Some embodiments contain 3 to 5 carbons. Some embodimentscontain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons.Examples include cyclopropanediyl, cyclobutanediyl, cyclopentanediyl,cyclohexanediyl, cycloheptanediyl, and the like. In some embodimentsC₃-C₇ cycloalkylene is selected from: 1,1-cyclopropanediyl,1,1-cyclobutanediyl, 1,1-cyclopentanediyl, 1,1-cyclohexanediyl,1,1-cycloheptanediyl, and the like. In some embodiments C₃-C₇cycloalkylene is selected from: 1,2-cyclopropanediyl,1,2-cyclobutanediyl, 1,2-cyclopentanediyl, 1,2-cyclohexanediyl,1,2-cycloheptanediyl, and the like.

The term “carbo-C₁-C₆-alkoxy” is intended to mean a C₁-C₆ alkyl ester ofa carboxylic acid, wherein C₁-C₆ alkyl has the same definition as foundherein. Examples include, but are not limited to, carbomethoxy[—C(O)OCH₃], carboethoxy, carbo-n-propoxy, carboisopropoxy,carbo-n-butoxy, carbo-s-butoxy, carbo-isobutoxy, carbo-t-butoxy,carbo-n-pentoxy, carbo-isopentoxy, carbo-t-pentoxy, carbo-neopentoxy,carbo-n-hexyloxy, and the like.

The term “carboxamide” is intended to mean the group —CONH₂.

The term “carboxy” is intended to mean the group —CO₂H; also referred toas a carboxylic acid group.

The term “cyano” is intended to mean the group —CN.

The term “C₂-C₈ dialkylamino” is intended to mean a radical comprisingan amino group substituted with two of the same or different C₁-C₄ alkylgroups, wherein C₁-C₄ alkyl has the same definition as found herein.Some examples include, but are not limited to, dimethylamino,methylethylamino, diethylamino, methylpropylamino, methylisopropylamino,ethylpropylamino, ethylisopropylamino, dipropylamino,propylisopropylamino, and the like. Some embodiments are C₂-C₄dialkylamino.

The term “C₂-C₈ dialkylsulfonamide” is intended to mean is intended tomean one of the following groups shown below:

wherein C₁-C₄ alkyl has the same definition as found herein.

The term “C₁-C₆ haloalkoxy” is intended to mean a radical comprising aC₁-C₆ haloalkyl group directly attached to an oxygen atom, wherein C₁-C₆haloalkyl has the same definition as found herein. Examples include, butare not limited to, difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.

The term “C₁-C₆ haloalkyl” is intended to mean a radical comprising aC₁-C₆ alkyl group substituted with one or more halogens, wherein C₁-C₆alkyl has the same definition as found herein. The C₁-C₆ haloalkyl maybe fully substituted in which case it can be represented by the formulaC_(n)L_(2n+1), wherein L is a halogen and “n” is 1, 2, 3, 4, 5 or 6.When more than one halogen is present then they may be the same ordifferent and selected from: fluorine, chlorine, bromine, and iodine. Insome embodiments, haloalkyl contains 1 to 5 carbons. In someembodiments, haloalkyl contains 1 to 4 carbons. In some embodiments,haloalkyl contains 1 to 3 carbons. In some embodiments, haloalkylcontains 1 or 2 carbons. Examples of haloalkyl groups include, but arenot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and thelike.

The term “halogen” is intended to mean to a fluoro, chloro, bromo oriodo group.

The term “heteroaryl” is intended to mean a ring system containing 5 to14 ring atoms, that may contain a single ring, two fused rings or threefused rings, and wherein at least one ring is aromatic and at least onering atom is a heteroatom selected from, for example: O, S and N,wherein N is optionally substituted with H, C₁-C₄ acyl, C₁-C₄ alkyl, oroxide (i.e., together with an aromatic ring nitrogen form an N-oxide).Some embodiments contain 5 to 6 ring atoms for example furanyl, thienyl,pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.Some embodiments contain 8 to 14 ring atoms for example quinolizinyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl,purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl. phenazinyl,phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl,1H-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl,isobenzofuran, 2,3-dihydrobenzofuranyl, 4H-benzo[1,3]dioxinyl,3,4-dihydro-1H-isoquinolinyl,1,4,6,7-tetrahydro-imidazo[4,5-c]pyridinyl,7,8-dihydro-5H-[1,6]naphthyridinyl,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, benzo[1,3]dioxolyl,pyrazolo[1,5-a]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, and the like.

The term “heteroarylene” is intended to mean is intended to mean anaromatic ring di-radical containing 5 to 14 ring atoms that may be asingle ring, two fused rings or three fused rings, wherein at least onearomatic ring atom is a heteroatom selected from, for example: O, S, andN, wherein N is optionally substituted with H, C₁-C₄ acyl, C₁-C₄ alkyl,or oxide (i.e., together with an aromatic ring nitrogen form anN-oxide). Some embodiments contain 5 to 6 ring atoms for examplefurandiyl, thiophenediyl, pyrrolediyl, imidazolediyl, oxazolediyl,thiazolediyl, isoxazolediyl, pyrazolediyl, isothiazolediyl,oxadiazolediyl, triazolediyl, thiadiazolediyl, pyridinediyl,pyrazinediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, and thelike. Some embodiments contain 8 to 14 ring atoms for examplequinolizinediyl, quinolinediyl, isoquinolinediyl, cinnolinediyl,phthalazinediyl, quinazolinediyl, quinoxalinediyl, triazinediyl,indolediyl, isoindolediyl, indazolediyl, indolizinediyl, purinediyl,naphthyridinediyl, pteridinediyl, carbazolediyl, acridinediyl.phenazinediyl, phenothiazinediyl, phenoxazinediyl, benzoxazolediyl,benzothiazolediyl, 1H-benzimidazolediyl, imidazopyridinediyl,benzothienediyl, benzofurandiyl, isobenzofurandiyl, and the like.

The term “heteroaryloxy” is intended to mean a radical comprising aheteroaryl group, attached to an oxygen, wherein heteroaryl has the samedefinition as found herein. The term “heterobicyclyl” is intended tomean a radical comprising two fused or bridged, non-aromatic ringscontaining 5 to 11 ring atoms wherein one, two, three or four ring atomsare heteroatoms selected from, for example: O, S, and N, wherein N issubstituted with H, C₁-C₄ acyl or C₁-C₄ alkyl, and S is optionallysubstituted with one or two oxygens. Examples of a heterobicyclyl groupinclude, but are not limited to, octahydropyrrolo[1,2-a]pyrazinyl,1-aza-bicyclo[2.2.2]octyl, 9-aza-bicyclo[3.3.1]nonyl, and the like.

The term “heterocyclyl” is intended to mean a non-aromatic ring radicalcontaining 3 to 8 ring atoms, wherein one, two or three ring atoms areheteroatoms selected from, for example: O, S, and N, wherein N issubstituted with H, C₁-C₄ acyl or C₁-C₄ alkyl, and S is optionallysubstituted with one or two oxygens. Examples of a heterocyclyl groupinclude, but are not limited to, aziridinyl, azetidinyl, piperidinyl,morpholinyl, piperazinyl, pyrrolidinyl, [1,3]-dioxolanyl,thiomorpholinyl, [1,4]oxazepanyl, 1,1-dioxothiomorpholinyl, azepanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl,1-oxo-hexahydro-1λ⁴-thiopyranyl, 1,1-dioxo-hexahydro-1λ⁶-thiopyranyl,and the like.

The term “heterocyclylene” is intended to mean a non-aromatic ringdi-radical containing 3 to 8 ring atoms, wherein one, two or three ringatoms are heteroatoms selected from, for example: O, S, and N, wherein Nis substituted with H, C₁-C₄ acyl or C₁-C₄ alkyl, and S is optionallysubstituted with one or two oxygens. Examples of a heterocyclylene groupinclude, but are not limited to, aziridinediyl, azetidinediyl,piperidinediyl, morpholinediyl, piperazinediyl, pyrrolidinediyl,[1,3]-dioxolanediyl, thiomorpholinediyl, [1,4]oxazepanediyl,1,1-dioxothiomorpholinediyl, azepanediyl, tetrahydrofurandiyl, and thelike.

The term “hydroxyl” is intended to mean the group —OH.

The term “phosphonooxy” is intended to mean the group —OP(O)(OH)₂.

The term “ureyl” is intended to mean the group —NH₂C(O)NH₂.

Administration of the compounds and pharmaceutically acceptable salts,solvates, hydrates, and/or N-oxides thereof described herein as the soleactive pharmaceutical agent (i.e., mono-therapy) is described inPCT/US2010/002360, filed Aug. 27, 2010, which is incorporated herein byreference in its entirety.

Provided is a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein for usein combination with and one or more known pharmaceutical agents selectedfrom analgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents. Also provided is a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein for use in combination with and one or moreknown pharmaceutical agents selected from analgesic agents andantidiabetic agents.

Provided is the use of a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents in the manufacture of a medicament for treating painin an individual. Also provided is the use of a compound of Formula Iaor a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents in themanufacture of a medicament for treating pain in an individual.

Provided is the use of a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents in the manufacture of a medicament for managing painin an individual. Also provided is the use of a compound of Formula Iaor a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents in themanufacture of a medicament for managing pain in an individual.

Provided is a composition comprising a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents, antidiabetic agents, osteoarthritisagents, and anticancer agents. Also provided is a composition comprisinga compound of Formula Ia or a pharmaceutically acceptable salt, solvate,hydrate, and/or N-oxide thereof described herein and one or more knownpharmaceutical agents selected from analgesic agents and antidiabeticagents.

Provided is a composition comprising a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidedescribed herein and one or more known pharmaceutical agents selectedfrom analgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents, and a pharmaceutically acceptable carrier. Alsoprovided is a composition comprising a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents, and apharmaceutically acceptable carrier.

Provided is a method for preparing a composition comprising the step ofadmixing a compound of Formula Ia or a pharmaceutically acceptable salt,solvate, hydrate, and/or N-oxide thereof described herein and one ormore known pharmaceutical agents selected from analgesic agents,antidiabetic agents, osteoarthritis agents, and anticancer agents. Alsoprovided is a composition obtained by a a method for preparing acomposition comprising the step of admixing a compound of Formula Ia ora pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents, antidiabetic agents, osteoarthritisagents, and anticancer agents. Also provided is a method for preparing acomposition comprising the step of admixing a compound of Formula Ia ora pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents. Also provided isa composition obtained by a method for preparing a compositioncomprising the step of admixing a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents.

Provided is a method for preparing a composition comprising the step ofadmixing a compound of Formula Ia or a pharmaceutically acceptable salt,solvate, hydrate, and/or N-oxide thereof described herein and one ormore known pharmaceutical agents selected from analgesic agents,antidiabetic agents, osteoarthritis agents, and anticancer agents, and apharmaceutically acceptable carrier. Also provided is a compositionobtained by a method for preparing a composition comprising the step ofadmixing a compound of Formula Ia or a pharmaceutically acceptable salt,solvate, hydrate, and/or N-oxide thereof described herein and one ormore known pharmaceutical agents selected from analgesic agents,antidiabetic agents, osteoarthritis agents, and anticancer agents, and apharmaceutically acceptable carrier.

Also provided is a method for preparing a composition comprising thestep of admixing a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and one or more known pharmaceutical agents selected fromanalgesic agents and antidiabetic agents. Also provided is a compositionobtained by a method for preparing a composition comprising the step ofadmixing a compound of Formula Ia or a pharmaceutically acceptable salt,solvate, hydrate, and/or N-oxide thereof described herein and one ormore known pharmaceutical agents selected from analgesic agents andantidiabetic agents.

In some embodiments, the compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and the one or more known pharmaceutical agents are admixed witha pharmaceutically acceptable carrier.

In some embodiments, the compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein compound of Formula Ia, or a pharmaceutically acceptable salt,solvate, hydrate, and/or N-oxide thereof and the one or more knownpharmaceutical agents are each admixed with a different pharmaceuticallyacceptable carrier.

The pharmaceutical carrier generally is compatible with the otheringredients in the composition and should be tolerated by the individualrecipient. Other physiologically active ingredients can be incorporatedinto the pharmaceutical composition if desired, and if such ingredientsare compatible with the other ingredients in the composition.Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants can be used intablets and capsules for oral administration.

Compositions for oral administration can be in the form of solutions,emulsions, aqueous or oily suspensions, and syrups. Alternatively, thecompositions for oral administration can be in the form of dry powderthat can be reconstituted with water or another suitable liquid vehiclebefore use. Additional additives such as suspending or emulsifyingagents, non-aqueous vehicles (including edible oils), preservatives, andflavorings and colorants can be added. Compositions for parenteraladministration can be prepared by dissolving the compounds in a suitableliquid vehicle and filter sterilizing the solution before filling andsealing an appropriate vial or ampoule. These are just a few examples ofthe many appropriate methods well known in the art for preparingcompositions for oral or parenteral administration.

Provided is a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein for usein a method for the treatment of pain in an individual in need thereof,comprising administering to said individual said compound and one ormore known pharmaceutical agents selected from analgesic agents,antidiabetic agents, osteoarthritis agents, and anticancer agents. Alsoprovided is a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein for usein a method for the treatment of pain in an individual in need thereof,comprising administering to said individual said compound and one ormore known pharmaceutical agents selected from analgesic agents andantidiabetic agents.

Provided is a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein for usein a method for the treatment of pain in an individual in need thereof,comprising prescribing to said individual said compound and one or moreknown pharmaceutical agents selected from analgesic agents, antidiabeticagents, osteoarthritis agents, and anticancer agents. Also provided is acompound of Formula Ia or a pharmaceutically acceptable salt, solvate,hydrate, and/or N-oxide thereof described herein for use in a method forthe treatment of pain in an individual in need thereof, comprisingprescribing to said individual said compound and one or more knownpharmaceutical agents selected from analgesic agents and antidiabeticagents.

Provided is a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein for usein a method for the management of pain in an individual in need thereof,comprising administering to said individual said compound and one ormore known pharmaceutical agents selected from analgesic agents,antidiabetic agents, osteoarthritis agents, and anticancer agents. Alsoprovided is a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein for usein a method for the management of pain in an individual in need thereof,comprising administering to said individual said compound and one ormore known pharmaceutical agents selected from analgesic agents andantidiabetic agents.

Provided is a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein for usein a method for the management of pain in an individual in need thereof,comprising prescribing to said individual said compound and one or moreknown pharmaceutical agents selected from analgesic agents, antidiabeticagents, osteoarthritis agents, and anticancer agents. Also provided is acompound of Formula Ia or a pharmaceutically acceptable salt, solvate,hydrate, and/or N-oxide thereof described herein for use in a method forthe management of pain in an individual in need thereof, comprisingprescribing to said individual said compound and one or more knownpharmaceutical agents selected from analgesic agents and antidiabeticagents.

Provided is one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents for use in combination with a compound of Formula Iaor a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein. Also provided is one or more knownpharmaceutical agents selected from analgesic agents and antidiabeticagents, for use in combination with a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein.

Provided is one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents for use in a method for the treatment of pain in anindividual in need thereof, said method comprises administering to saidindividual one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents and a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein. Also provided is one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents for use in amethod for the treatment of pain in an individual in need thereof, saidmethod comprises administering to said individual one or more knownpharmaceutical agents selected from analgesic agents and antidiabeticagents and a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein.

Provided is one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents for use in a method for the treatment of pain in anindividual in need thereof, said method comprises prescribing to saidindividual one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents and a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein. Also provided is one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents for use in amethod for the treatment of pain in an individual in need thereof, saidmethod comprises prescribing to said individual one or more knownpharmaceutical agents selected from analgesic agents and antidiabeticagents and a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein.

Provided is one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents for use in a method for the management of pain in anindividual in need thereof, said method comprises administering to saidindividual one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents and a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein. Also provided is one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents for use in amethod for the management of pain in an individual in need thereof, saidmethod comprises administering to said individual one or more knownpharmaceutical agents selected from analgesic agents and antidiabeticagents and a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein.

Provided is one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents for use in a method for the management of pain in anindividual in need thereof, said method comprises administering to saidindividual one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents and a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein. Also provided is one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents for use in amethod for the management of pain in an individual in need thereof, saidmethod comprises administering to said individual one or more knownpharmaceutical agents selected from analgesic agents and antidiabeticagents and a compound of Formula Ia or a pharmaceutically acceptablesalt, solvate, hydrate, and/or N-oxide thereof described herein.

Provided is a pharmaceutical product selected from: a pharmaceuticalcomposition, a formulation, a dosage form, a combined preparation, atwin pack, and a kit; comprising a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents, antidiabetic agents, osteoarthritisagents, and anticancer agents; for treating pain in an individual. Alsoprovided is a pharmaceutical product selected from: a pharmaceuticalcomposition, a formulation, a dosage form, a combined preparation, atwin pack, and a kit; comprising a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents; for treatingpain in an individual.

Provided is a pharmaceutical product selected from: a pharmaceuticalcomposition, a formulation, a dosage form, a combined preparation, atwin pack, and a kit; comprising a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents, antidiabetic agents, osteoarthritisagents, and anticancer agents; for managing pain in an individual. Alsoprovided is a pharmaceutical product selected from: a pharmaceuticalcomposition, a formulation, a dosage form, a combined preparation, atwin pack, and a kit; comprising a compound of Formula Ia or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and one or more known pharmaceutical agentsselected from analgesic agents and antidiabetic agents.

In some embodiments, the pharmaceutical product comprises apharmaceutical composition.

In some embodiments, the pharmaceutical product comprises a formulation.

In some embodiments, the pharmaceutical product comprises a dosage form.

In some embodiments, the pharmaceutical product comprises a combinedpreparation.

In some embodiments, the pharmaceutical product comprises a twin pack.

In some embodiments, the pharmaceutical product comprises a kit.

In some embodiments, the kit comprises a first package comprising acompound of Formula Ia or a pharmaceutically acceptable salt, solvate,hydrate, and/or N-oxide thereof described herein or a pharmaceuticalcomposition thereof, and a second package comprising one or more knownpharmaceutical agents selected from analgesic agents, antidiabeticagents, osteoarthritis agents, and anticancer agents or a pharmaceuticalcomposition thereof. In some embodiments, the kit comprises a firstpackage comprising a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein or a pharmaceutical composition thereof, and a second packagecomprising one or more known pharmaceutical agents selected fromanalgesic agents and antidiabetic agents.

Provided is a method for the treatment of pain in an individual in needthereof, comprising administering to said individual, a therapeuticallyeffective amount of a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents.

Provided is a method for the treatment of pain in an individual in needthereof, comprising prescribing to said individual, a therapeuticallyeffective amount of a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents.

Provided is a method for the management of pain in an individual in needthereof, comprising administering to said individual, a therapeuticallyeffective amount of a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents.

Provided is a method for the management of pain in an individual in needthereof, comprising prescribing to said individual, a therapeuticallyeffective amount of a compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and one or more known pharmaceutical agents selected fromanalgesic agents, antidiabetic agents, osteoarthritis agents, andanticancer agents.

In some embodiments, the individual is a human.

In some embodiments, the one or more known pharmaceutical agents areadministered to the individual simultaneously, separately, orsequentially.

In some embodiments, the compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and the one or more known pharmaceutical agents are administeredsimultaneously.

In some embodiments, the compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and the one or more known pharmaceutical agents are administeredseparately.

In some embodiments, the compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof describedherein and the one or more known pharmaceutical agents are administeredsequentially.

In some embodiments, the amount of the compound of Formula Ia, or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein alone and the amount of the one or more knownpharmaceutical agents alone are therapeutically ineffective.

In some embodiments, the combination of a compound of Formula Ia, or apharmaceutically acceptable salt, solvate, hydrate, and/or N-oxidethereof described herein and the one or more known pharmaceutical agentsresults in a supra additive or synergistic effect on relief of pain(see, e.g., FIG. 15). A synergistic effect means that the effect onpain, as demonstrated, e.g., by an increase in PWT or another measure ofpain intensity or severity as described herein, observed with thecombination therapy is greater than that seen by adding the effect onpain of each compound together. One advantage of using a synergisticcombination therapy is that less of each compound is required to achievea significant effect on pain and so fewer side effects can result fromtreatment. In some cases, side effects are not seen at the lower dosesused. Also, in some cases, the side effect profile of one drug canmitigate or average out the side effect profile of the other drug. Forexample, one of the drugs may result in increased blood pressure and theother drug results in lowered blood pressure so that the combinationtherapy does not effect blood pressure. Another potential advantage ofcombination therapy is that, since less compound is required, the costof therapy can be reduced.

In some embodiments, the pain is chosen from bone and joint pain, painassociated with osteoarthritis, hyperalgesia, allodynia, inflammatorypain, inflammatory hyperalgesia, neuropathic pain, neuropathichyperalgesia, acute nociception, muscle pain, dental pain, migraine andother headache pain, pain that occurs as an adverse effect oftherapeutics in an individual, and pain associated with a disorderselected from: cancer, multiple sclerosis, allergic reactions, nephriticsyndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia,HIV related-neuropathy, sciatica, and autoimmune conditions.

In some embodiments, the pain is chosen from bone and joint pain, painassociated with osteoarthritis, muscle pain, dental pain, migraine andother headache pain, inflammatory pain, neuropathic pain, pain thatoccurs as an adverse effect of therapeutics, pain associated withosteoarthritis; pain associated cancer, hyperalgesia; allodynia;inflammatory hyperalgesia; neuropathic hyperalgesia; and acutenociception.

In some embodiments, the pain is mild to moderate pain.

In some embodiments, pain is moderate to moderately severe pain.

In some embodiments, the individual has a visual analogue scale painscore of ≧40 mm.

In some embodiments, the individual has a Likert numerical rating scalepain score of ≧4.

In some embodiments, the pain is moderate to severe pain requiringcontinuous, around-the-clock opioid therapy an extended period of time.

In some embodiments, the pain is acute pain.

In some embodiments, the method is for short-term use (five days orless).

In some embodiments, the pain is chronic pain.

Suitable pharmaceutical agents that can be used in combination with thecompounds described herein include analgesic agents, antidiabeticagents, osteoarthritis agents, and anticancer agents.

In some embodiments, the analgesic agent is chosen from non-opioiddrugs, opioid drugs, and co-analgesic medications.

In some embodiments, the non opioid drug is chosen from non steroidalanti-inflammatory agents, choline magnesium trisalicylate,sulfasalazine, olsalazin, phenacetin, tenoxicam, phenylbutazone,oxyphenthartazone, tapentadol, celecoxib, etoricoxib, lumiracoxib,rofecoxib, parecoxib, and ziconotide.

In some embodiments, the non steroidal anti-inflammatory agent is chosenfrom acemetacin, acetaminophen, aminoprofen, aspirin, benoxaprofen,bucloxic acid, carprofen, choline magnesium salicylate, cholinesalicylate, clidanac, diclofenac, diflunisal, diflurisal, etodolac,fenoprofen, fenoprofen calcium, fentiazac, flosulide, flubufen,flufenamic acid, flufenisal, flurbiprofen, fluprofen, ibuprofen,indoprofen, indomethacin, isoxicam, ketoprofen, ketorolac tromethamine,lornoxicam, magnesium salicylate, meclofenamic acid, meclofenamatesodium, mefenamic acid, meloxicam, muroprofen, nabumetone, naproxen,nepafenac, niflumic acid, nimesulide, oxaprozin, oxpinac, piroprofen,piroxicam, pramoprofen, ramifenazone, salsalate, salicylsalicylic acid,sodium salicylate, sudoxicam, sulindac, suprofen, tiaprofenic acid,tiopinac, tolfenamic acid, tolmetin, trioxaprofen, zidometacin, andzomepirac.

In some embodiments, the opioid drug is chosen from alfentanil,allylprodine, alphaprodine, anileridine, apomorphine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide,diamorphone, dihydrocodeine, dihydrocodeinone enol acetate,dihydromorphine, dilaudid, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodeine, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, 6-monoacetylmorphine, morphine,morphine-6-glucuronide, myrophine, nalbuphine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,noscapine, opium, oxycodone, oxymorphone, papavereturn, papverine,pentazocine, pethidine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, proheptazine, promedol,properidine, propiram, propoxyphene, sufentanil, tilidine, and tramadol.

In some embodiments, the at least one analgesic agent comprises an NSAIDand an opiod drug.

In some embodiments, the at least one analgesic agent is chosen fromvicodin (acetaminophen and hydrocodone), percocet (oxycodone andacetaminophen), norco (hydrocodone bitartrate and acetaminophen), lorcet(acetaminophen and hydrocodone), darvocet (acetaminophen andpropoxyphene), and percodan (aspirin and oxycodone).

In some embodiments, the at least one analgesic agent is at least oneco-analgesic medication chosen from antidepressants, anti-anxietymedications, migraine medications, and gabapentin.

In some embodiments, the migraine medication is chosen from alpiropride,dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine,ergot, ergotamine, flumedroxone acetate, fonazine, lisuride, lomerizine,methysergide oxetorone, and pizotyline.

In some embodiments, the antidepressant is chosen from escitalopram,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

In some embodiments, the anti-anxiety medication is chosen fromalprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam,halazepam, lorazepam, oxazepam, and prazepam, buspirone; andbarbituates.

In some embodiments, the pain is neuropathic pain associated withdiabetic peripheral neuropathy.

In some embodiments, the one or more known pharmaceutical agents ischosen from antidiabetic agents.

In some embodiments, the antidiabetic agent is chosen from sulfonylurea,meglitinide, biguanide, alpha-glucosidase inhibitor, thizaolidinedione,insulin analog, and chromium picolinate/biotin.

In some embodiments, the antidiabetic agent is a sulfonylurea chosenfrom glibenclamide, glipizide, gliclazide, and glimepiride.

In some embodiments, the antidiabetic agent is a meglitinide chosen fromrepaglinide and nateglinide.

In some embodiments, the antidiabetic agent is a biguanide chosen frommetformin.

In some embodiments, the antidiabetic agent is an alpha-glucosidaseinhibitor chosen from acarbose, epalrestat, miglitol, and voglibose.

In some embodiments, the antidiabetic agent is a thizaolidinedionechosen from rosiglitazone and pioglitazone.

In some embodiments, the antidiabetic agent is insulin or an analogthereof chosen from insulin lispro, insulin aspart, and insulinglargine.

In some embodiments, the pain is pain associated with osteoarthritis.

In some embodiments, the one or more known pharmaceutical agents ischosen from osteoarthritis agents.

In some embodiments, the osteoarthritis agent is chosen from localizedinjections, topical patches, creams and gels, glucosamine, chondroitinsulfate, and vitamins.

In some embodiments, the localized injection is chosen from acorticosteroid injection and an injection of hyaluronan.

In some embodiments, the topical patches, creams and gels are chosenfrom civamide patch, diclofenac patch, topical strontium chloridehexahydrate, diclofenac sodium topical solution, capsaicin cream andmethylsalicylate cream.

In some embodiments, the osteoarthritis agent is chosen from valdecoxib,meloxicam, etodolac, naproxen sodium, diacerhein, tetracycline,antimalarial therapies, Gen-S, JNJ-39439335, JNJ-42160443 (a monoclonalantibody against nerve growth factor (NGF)), JNS013 (combination oftramadol and acetaminophen), ABT-102(N-[5-tert-butyl-2,3-dihydro-1H-inden-1(R)-yl]-N′-(1H-indazol-4-yl)urea),SAR114137, MEDI-578, LY545694 (iGluR5 antagonist), BEMA buprenorphine(CA Index Name: 6,14-ethenomorphinan-7-methanol,17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-,(αS,5α,7α)-hydrochloride), GRC 15300, PH-797804 (CA Index Name:benzamide,3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxo-1(2H)-pyridinyl]-N,4-dimethyl-),ADX71943, ELI-216 (combination of oxycodone and naltrexone), NT-11624(CA Index Name: 1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione, dihydro-),diractin, XEN 402 (a voltage-gated Na(V)1.7 sodium channel blocker), CRB0022 (a monoclonal antibody against nerve growth factor (NGF)),apitoxin, and etoricoxib.

The osteoarthritis agent ABT-102 isN-[5-tert-butyl-2,3-dihydro-1H-inden-1(R)-yl]-N′-(1H-indazol-4-yl)urea,and the chemical structure is:

The osteoarthritis agent BEMA buprenorphine has the CA Index Name:6,14-ethenomorphinan-7-methanol,17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-,(αS,5α,7α)-hydrochloride, and the chemical structure is:

The osteoarthritis agent PH-797804 has the CA Index Name: benzamide,3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxo-1(2H)-pyridinyl]-N,4-dimethyl-), and the chemical structure is:

The osteoarthritis agent NT-11624 has the CA Index Name:1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione, dihydro-), and the chemicalstructure is:

In some embodiments, pain is pain associated with cancer.

In some embodiments, the pain is breakthrough pain in cancer patient.

In some embodiments, the individual is already receiving and is tolerantto opioid therapy for the cancer pain.

In some embodiments, the one or more known pharmaceutical agents ischosen from anticancer agents.

In some embodiments, the pain is pain that occurs as an adverse effectof the anticancer agent.

In some embodiments, the anticancer agent is paclitaxel.

In some embodiments, the cancer is chosen from prostrate cancer,pancreatic cancer, lung cancer, and breast cancer.

In some embodiments, the cancer is chosen from pancreatic cancer, lungcancer, and breast cancer.

In some embodiments, the anticancer agent is chosen from acivicin,aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin,altretamine, ambomycin, ametantrone acetate, aminoglutethimide,amsacrine, anastrozole, anthramycin, asparaginase, asperlin,azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide,bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycinsulfate, brequinar sodium, bropirimine, busulfan, cactinomycin,calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicinhydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin,cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine,dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine,dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel,doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifenecitrate, dromostanolone propionate, duazomycin, edatrexate, eflornithinehydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine,epirubicin hydrochloride, erbulozole, esorubicin hydrochloride,estramustine, estramustine phosphate sodium, etanidazole, etoposide,etoposide phosphate, etoprine, fadrozole hydrochloride, fazarabine,fenretinide, floxuridine, fludarabine phosphate, fluorouracil,fluorocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabinehydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide,ilmofosine, interleukin II (including recombinant interleukin II orrIL2), interferon alfa-2a, interferon alfa-2b, interferon alfa-n1,interferon alfa-n3, interferon beta-I a, interferon gamma-I b,iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole,leuprolide acetate, liarozole hydrochloride, lometrexol sodium,lomustine, losoxantrone hydrochloride, masoprocol, maytansine,mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate,melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium,metoprine, meturedepa, mitindomide, mitocarcin, mitocromin, mitogillin,mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride,mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran,paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate,perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride,plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine,procarbazine hydrochloride, puromycin, puromycin hydrochloride,pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride,semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermaniumhydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin,sulofenur, talisomycin, tecogalan sodium, tegafur, teloxantronehydrochloride, temoporfin, teniposide, teroxirone, testolactone,thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifenecitrate, trestolone acetate, triciribine phosphate, trimetrexate,trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uracilmustard, uredepa, vapreotide, verteporfin, vinblastine sulfate,vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate,vinglycinate sulfate, vinleurosine sulfate, vinorelbine tartrate,vinrosidine sulfate, vinzolidine sulfate, vorozole, zeniplatin,zinostatin, and zorubicin hydrochloride.

In some embodiments, the anticancer agent is chosen from 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix; antidorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma;antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolinglycinate; apoptosis gene modulators; apoptosis regulators; apurinicacid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A;collismycin B; combretastatin A4; combretastatin analogue; conagenin;crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives;curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabineocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine;dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide;dexrazoxane; dexverapamil; diaziquone; didemnin B; didox;diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol; 9-dioxamycin;diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor-1 based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinusderived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

In some embodiments, the anticancer agent is chosen from eribulinmesylate, cabazitaxel, sipuleucel-T, degarelix, raloxifene, topotecanhydrochloride, ixabepilone, lapatinib, erlotinib, gefitinib, abarelix,leuprolide acetate, fulvestrant, letrozole, triptorelin pamoate,herceptin, nolvadex, photofrin, xeloda, letrozole, anastrozole,flutamide, gemcitabine HCl, docetaxel, goserelin acetate, bevacizumab,celecoxib, cetuximab, denosumab, ibandronic acid, thyrotropin alfa,trabectedin, and Pemetrexed.

Other pharmaceutical agents are well known, or will be readily apparentin light of the instant disclosure, to one of ordinary skill in the art.

It is understood that the scope of combination-therapy of the compoundof Formula Ia or a pharmaceutically acceptable salt, solvate, andhydrate thereof described herein with other pharmaceutical agents is notlimited to those listed herein but includes in principle any combinationwith any pharmaceutical agent or pharmaceutical composition useful forthe treatment of diseases, conditions or disorders that are linked topain.

Provided are certain compounds as shown in Formula Ia andpharmaceutically acceptable salts, solvates, hydrates, and/or N-oxidesthereof:

wherein:

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently selected from: H andC₁-C₆ alkyl;

X is NR⁷ and Y is CC(O)N(R⁸)R⁹; or

X is CC(O)N(R⁸)R⁹ and Y is NR⁷;

R⁷ is —R¹⁰—R¹¹—R¹²—R¹³; wherein:

R¹⁰ is selected from: C₁-C₆ alkylene, heteroarylene, andheterocyclylene; or R¹⁰ is absent;

R¹¹ is selected from: —C(O)NH— and C₁-C₆ alkylene; or R¹¹ is absent;

R¹² is C₁-C₆ alkylene; or R¹² is absent; and

R¹³ is selected from: C₁-C₆ alkyl, aryl, C₃-C₇ cycloalkyl, heteroaryl,heterocyclyl, and hydroxyl; wherein said C₁-C₆ alkyl, aryl, andheteroaryl are each optionally substituted with one or two substituentsselected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylsulfonyl, amino, C₃-C₇ cycloalkyl, cyano, C₂-C₈ dialkylamino, C₁-C₆haloalkyl, halogen, and hydroxyl;

R⁸ is —R¹⁴—R¹⁵—R¹⁶—R¹⁷; wherein:

R¹⁴ is selected from: C₁-C₆ alkylene, C₃-C₇ cycloalkenylene, C₃-C₇cycloalkylene, heteroarylene, and heterocyclylene; wherein said C₁-C₆alkylene and heterocyclylene are each optionally substituted with one ormore substituents selected from: C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, aryl, carboxy, heteroaryl, heterocyclyl, and hydroxyl;wherein said C₁-C₆ alkyl and aryl are optionally substituted with onesubstituent selected from: C₁-C₆ alkoxy, aryl, halogen, heteroaryl, andhydroxyl; or R¹⁴ is absent;

R¹⁵ is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C₁-C₆ alkylene, C₃-C₇cycloalkylene, heteroarylene, and heterocyclylene; wherein saidheterocyclylene is optionally substituted with C₁-C₆ alkyl; or R¹⁵ isabsent;

R¹⁶ is C₁-C₆ alkylene; or R¹⁶ is absent; and

R¹⁷ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino,C₁-C₆ alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino, aryl, arylamino,arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano,C₃-C₇ cycloalkyl, C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈dialkylamino, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkyl, heteroaryl,heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy;wherein said C₁-C₆ alkylamino, amino, aryl, arylamino, aryloxy, C₅-C₁₁bicycloalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylamino, heteroaryl,heterobicyclyl, heterocyclyl, and ureyl are each optionally substitutedwith one or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, amino, aryl, carboxy,cyano, C₃-C₇ cycloalkyl, C₂-C₈ dialkylamino, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and

R⁹ is selected from H, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; or

R⁸ and R⁹ together with the nitrogen atom to which they are both bondedform a group selected from: heterocyclyl and heterobicyclyl, eachoptionally substituted with one or more substituents selected from:Carbo-C₁-C₆-alkoxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, carbo-C₁-C₆-alkoxy,C₁-C₆ haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, andhydroxyl; wherein said aryl, C₁-C₆ alkyl, and heteroaryl are optionallysubstituted with one substituent selected from: C₃-C₇ cycloalkyl, C₁-C₆alkoxy, halogen, and hydroxyl.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g.,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, X, and Y) contained within the generic chemical formulae describedherein, for example, Ia and Ie, etc., are specifically embraced by thepresent invention just as if each and every combination was individuallyexplicitly recited, to the extent that such combinations embracecompounds that result in stable compounds (i.e., compounds that can beisolated, characterized and tested for biological activity). Inaddition, all subcombinations of the chemical groups listed in theembodiments describing such variables, as well as all subcombinations ofuses and medical indications described herein, are also specificallyembraced by the present invention just as if each and everysubcombination of chemical groups and subcombination of uses and medicalindications was individually and explicitly recited, to the extent thatsuch combinations embrace compounds that result in stable compounds(i.e., compounds that can be isolated, characterized and tested forbiological activity). In addition, all subcombinations of the chemicalgroups listed in the embodiments describing such variables, as well asall subcombinations of uses and medical indications described herein,are also specifically embraced by the present invention just as if eachand every subcombination of chemical groups and subcombination of usesand medical indications was individually and explicitly recited herein.In addition, some embodiments include every combination of the one ormore known pharmaceutical agents either specifically disclosed herein orspecifically disclosed in any reference recited herein just as if eachand every combination was individually and explicitly recited. Stillfurther, some embodiments of the present invention include everycombination of one or more embodiments pertaining to the chemical groupsrepresented by the variables and generic chemical formulae as describedherein or every combination of one or more compounds of Formula (Ia)together/in combination with every combination of the one or more knownpharmaceutical agents either specifically disclosed herein orspecifically disclosed in any reference recited herein just as if eachand every combination was individually and explicitly recited.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents, and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one group they can be identical or they canbe different.

Compounds described herein can also include tautomeric forms, such asketo-enol tautomers and the like. Tautomeric forms can be in equilibriumor sterically locked into one form by appropriate substitution. It isunderstood that the various tautomeric forms are within the scope of thecompounds described herein.

The present disclosure includes all isotopes of atoms occurring in thepresent compounds, salts and crystalline forms thereof. Compoundsdescribed herein can also include all isotopes of atoms occurring in theintermediates and/or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example, and without limitation, isotopes of hydrogen include ²H(deuterium) and ³H (tritium). Isotopes of carbon include ¹³C and ¹⁴C.

It is understood and appreciated that compounds of Formula Ia andformulae related thereto may have one or more chiral centers andtherefore can exist as enantiomers and/or diastereoisomers. Theinvention is understood to extend to and embrace all such enantiomers,diastereoisomers and mixtures thereof, including but not limited toracemates. It is understood that compounds of Formula Ia and formulaeused throughout this disclosure are intended to represent all individualenantiomers and mixtures thereof, unless stated or shown otherwise.

The Group R¹:

In some embodiments, R¹ is selected from: H and C₁-C₆ alkyl.

In some embodiments, R¹ is H.

In some embodiments, R¹ is C₁-C₆ alkyl.

In some embodiments, R¹ is methyl.

In some embodiments, R¹ is isopropyl.

The Group R²:

In some embodiments, R² is selected from: H and C₁-C₆ alkyl.

In some embodiments, R² is H.

In some embodiments, R² is C₁-C₆ alkyl.

In some embodiments, R² is methyl.

In some embodiments, R² is isopropyl.

The Group R³:

In some embodiments, R³ is selected from: H and C₁-C₆ alkyl.

In some embodiments, R³ is H.

In some embodiments, R³ is C₁-C₆ alkyl.

In some embodiments, R³ is methyl.

In some embodiments, R³ is isopropyl.

The Group R⁴:

In some embodiments, R⁴ is selected from: H and C₁-C₆ alkyl.

In some embodiments, R⁴ is H.

In some embodiments, R⁴ is C₁-C₆ alkyl.

In some embodiments, R⁴ is methyl.

In some embodiments, R⁴ is isopropyl.

The Group R⁵:

In some embodiments, R⁵ is selected from: H and C₁-C₆ alkyl.

In some embodiments, R⁵ is H.

In some embodiments, R⁵ is C₁-C₆ alkyl.

In some embodiments, R⁵ is methyl.

In some embodiments, R⁵ is isopropyl.

The Group R⁶:

In some embodiments, R⁶ is selected from: H and C₁-C₆ alkyl.

In some embodiments, R⁶ is H.

In some embodiments, R⁶ is C₁-C₆ alkyl.

In some embodiments, R⁶ is methyl.

In some embodiments, R⁶ is isopropyl.

The Group X:

In some embodiments, X is NR⁷; wherein R⁷ is —R¹⁰—R¹¹—R¹²—R¹³

In some embodiments, X is CCONR⁸R⁹.

In some embodiments, X is CC(O)NHR⁸.

The Group Y:

In some embodiments, Y is NR⁷; wherein R⁷ is —R¹⁰—R¹¹—R¹²—R¹³

In some embodiments, Y is CCONR⁸R⁹.

In some embodiments, Y is CC(O)NHR⁸.

The Group R⁷:

In some embodiments, R⁷ is —R¹⁰—R¹¹—R¹²—R¹³, or an N-oxide thereof.

In some embodiments, R⁷ is —R¹⁰—R¹¹—R¹²—R¹³.

In some embodiments, R⁷ is selected from: aryl and heteroaryl; whereinsaid aryl and heteroaryl are each optionally substituted with one or twosubstituents selected from: cyano and halogen.

In some embodiments, R⁷ is selected from: aryl and heteroaryl; whereinsaid aryl and heteroaryl are each optionally substituted with one or twosubstituents selected from: fluoro, chloro, and cyano.

In some embodiments, R⁷ is selected from: 2,4-difluoro-phenyl,2,4-dichloro-phenyl, 5-chloro-pyridin-2-yl, 5-cyano-pyrazin-2-yl,pyrazin-2-yl, 5-fluoro-pyridin-2-yl, 4-chloro-pyridin-2-yl,4-fluoro-pyridin-2-yl, 4-cyano-pyridin-2-yl, and 4-oxy-pyrazin-2-yl.

In some embodiments, R⁷ is selected from: 2,4-difluoro-phenyl,2,4-dichloro-phenyl, 5-chloro-pyridin-2-yl, 5-cyano-pyrazin-2-yl,pyrazin-2-yl, 5-fluoro-pyridin-2-yl, 4-chloro-pyridin-2-yl,4-fluoro-pyridin-2-yl, 4-cyano-pyridin-2-yl, and 4-oxy-pyrazin-2-yl.

In some embodiments, R⁷ is selected from: 2,4-difluoro-phenyl,5-bromo-pyridin-2-yl, 4-cyano-phenyl, pyridin-3-yl, pyridin-2-yl,5-thiazol-2-yl-pyridin-2-yl, 5-trifluoromethyl-pyridin-2-yl,5-o-tolyl-pyridin-2-yl, 5-dimethylamino-pyrazin-2-yl,2,4-dichloro-phenyl, 5-isopropyl-pyridin-2-yl, 5-methyl-pyridin-2-yl,5-(4-methoxy-phenyl)-pyridin-2-yl, 2-fluoro-4-methanesulfonyl-phenyl,2-fluoro-phenyl, 5-chloro-pyridin-2-yl, 5-bromo-pyridin-3-yl,tert-butyl, 2-methoxy-pyridin-4-yl, 2,2-dimethyl-propyl,tetrahydro-pyran-4-ylmethyl, phenyl, 4-trifluoromethyl-pyridin-2-yl,6-chloro-pyrazin-2-yl, 1-oxo-hexahydro-1 ⁴-thiopyran-4-yl,5-morpholin-4-yl-pyridin-2-yl, 6-bromo-pyridin-3-yl,5-methoxy-pyridin-2-yl, 5,6-difluoro-pyridin-3-yl,6-methoxy-pyridazin-3-yl, 2-chloro-pyridin-4-yl,5-cyclopropyl-pyrazin-2-yl, 1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl,1-benzyl-piperidin-4-yl, 6-cyano-pyrazin-2-yl,2-hydroxy-2-methyl-propyl, 4-fluoro-phenyl, 5-ethyl-pyridin-2-yl,isopropyl, 5-phenyl-pyridin-2-yl, pyridin-4-yl, 2,5-difluoro-phenyl,3-fluoro-phenyl, pyrimidin-4-yl, 2-(tetrahydro-pyran-4-yl)-ethyl,3,5-difluoro-pyridin-2-yl, pyrazin-2-yl, tetrahydro-thiopyran-4-yl,5-p-tolyl-pyridin-2-yl, 4-methoxy-phenyl, 2-morpholin-4-yl-ethyl,5-cyano-pyridin-2-yl, 5-cyano-pyrazin-2-yl,6′-methyl-[3,3′]bipyridinyl-6-yl, 6-chloro-pyridazin-3-yl,5-fluoro-pyridin-2-yl, 5-ethyl-pyrazin-2-yl, 6-methoxy-pyrazin-2-yl,5-dimethylamino-pyridin-2-yl, 1-(4-fluoro-phenyl)-1-methyl-ethyl,5-pyrimidin-5-yl-pyridin-2-yl, 4-methyl-pyridin-2-yl,5-methoxy-pyrazin-2-yl, 5-propyl-pyridin-2-yl, 6-chloro-pyridin-3-yl,5-m-tolyl-pyridin-2-yl, 5-hydroxy-pyrazin-2-yl,cyclopropyl-pyridin-2-yl, 2,6-difluoro-phenyl, 3-fluoro-pyridin-4-yl,5-isopropyl-pyrazin-2-yl, 5-bromo-pyrazin-2-yl,5-cyclopentyl-pyridin-2-yl, o-tolyl, 4-fluoro-benzyl,3-methyl-pyridin-2-yl, 6-methyl-4-trifluoromethyl-pyridin-2-yl,6-dimethylamino-pyrazin-2-yl, 1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl,5-(4-fluoro-phenyl)-pyridin-2-yl, 5-cyclopropyl-pyridin-2-yl,6-ethyl-pyrazin-2-yl, 5-methylamino-pyrazin-2-yl, 5-methyl-pyrazin-2-yl,3-fluoro-pyridin-2-yl, 5-cyclobutyl-pyrazin-2-yl, 5-ethoxy-pyrazin-2-yl,5-trifluoromethyl-pyrazin-2-yl, 5-cyano-pyridin-3-yl,5-cyclopropylmethyl-pyrazin-2-yl, 5-pentafluoroethyl-pyrazin-2-yl,5-heptafluoropropyl-pyrazin-2-yl, 5-chloro-4-methyl-pyridin-2-yl,5-chloro-4-trifluoromethyl-pyridin-2-yl, 4-bromo-pyridin-2-yl,4-chloro-pyridin-2-yl, 4-fluoro-pyridin-2-yl, 4-oxy-pyrazin-2-yl,4-cyclopropyl-pyridin-2-yl, 4-cyano-pyridin-2-yl,4-methanesulfonyl-pyridin-2-yl, 4-methoxy-pyridin-2-yl, piperidin-4-yl,tetrahydro-pyran-4-yl, 3-methyl-1,1-dioxo-tetrahydro-1λ⁶ thiophen-3-yl,5-chloro-3-fluoro-pyridin-2-yl, 3-fluoro-5-methoxy-pyridin-2-yl,2-chloro-4-fluoro-phenyl, 6-fluoro-pyridin-3-yl, 6-cyano-pyridin-3-yl,3-hydroxy-3-methyl-butyl, 4-iodo-pyridin-2-yl, 1-oxy-pyridin-3-yl,4-tert-butylcarbamoyl-pyridin-2-yl, and 4-hydroxy-pyridin-2-yl.

In some embodiments, R⁷ is selected from: 2,4-difluoro-phenyl,5-bromo-pyridin-2-yl, 4-cyano-phenyl, pyridin-3-yl, pyridin-2-yl,5-thiazol-2-yl-pyridin-2-yl, 5-trifluoromethyl-pyridin-2-yl,5-o-tolyl-pyridin-2-yl, 5-dimethylamino-pyrazin-2-yl,2,4-dichloro-phenyl, 5-isopropyl-pyridin-2-yl, 5-methyl-pyridin-2-yl,5-(4-methoxy-phenyl)-pyridin-2-yl, 2-fluoro-4-methanesulfonyl-phenyl,2-fluoro-phenyl, 5-chloro-pyridin-2-yl, 5-bromo-pyridin-3-yl,tert-butyl, 2-methoxy-pyridin-4-yl, 2,2-dimethyl-propyl,tetrahydro-pyran-4-ylmethyl, phenyl, 4-trifluoromethyl-pyridin-2-yl,6-chloro-pyrazin-2-yl, 1-oxo-hexahydro-1 ⁴-thiopyran-4-yl,5-morpholin-4-yl-pyridin-2-yl, 6-bromo-pyridin-3-yl,5-methoxy-pyridin-2-yl, 5,6-difluoro-pyridin-3-yl,6-methoxy-pyridazin-3-yl, 2-chloro-pyridin-4-yl,5-cyclopropyl-pyrazin-2-yl, 1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl,1-benzyl-piperidin-4-yl, 6-cyano-pyrazin-2-yl,2-hydroxy-2-methyl-propyl, 4-fluoro-phenyl, 5-ethyl-pyridin-2-yl,isopropyl, 5-phenyl-pyridin-2-yl, pyridin-4-yl, 2,5-difluoro-phenyl,3-fluoro-phenyl, pyrimidin-4-yl, 2-(tetrahydro-pyran-4-yl)-ethyl,3,5-difluoro-pyridin-2-yl, pyrazin-2-yl, tetrahydro-thiopyran-4-yl,5-p-tolyl-pyridin-2-yl, 4-methoxy-phenyl, 2-morpholin-4-yl-ethyl,5-cyano-pyridin-2-yl, 5-cyano-pyrazin-2-yl,6′-methyl-[3,3′]bipyridinyl-6-yl, 6-chloro-pyridazin-3-yl,5-fluoro-pyridin-2-yl, 5-ethyl-pyrazin-2-yl, 6-methoxy-pyrazin-2-yl,5-dimethylamino-pyridin-2-yl, 1-(4-fluoro-phenyl)-1-methyl-ethyl,5-pyrimidin-5-yl-pyridin-2-yl, 4-methyl-pyridin-2-yl,5-methoxy-pyrazin-2-yl, 5-propyl-pyridin-2-yl, 6-chloro-pyridin-3-yl,5-m-tolyl-pyridin-2-yl, 5-hydroxy-pyrazin-2-yl,cyclopropyl-pyridin-2-yl, 2,6-difluoro-phenyl, 3-fluoro-pyridin-4-yl,5-isopropyl-pyrazin-2-yl, 5-bromo-pyrazin-2-yl,5-cyclopentyl-pyridin-2-yl, o-tolyl, 4-fluoro-benzyl,3-methyl-pyridin-2-yl, 6-methyl-4-trifluoromethyl-pyridin-2-yl,6-dimethylamino-pyrazin-2-yl, 1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl,5-(4-fluoro-phenyl)-pyridin-2-yl, 5-cyclopropyl-pyridin-2-yl,6-ethyl-pyrazin-2-yl, 5-methylamino-pyrazin-2-yl, 5-methyl-pyrazin-2-yl,3-fluoro-pyridin-2-yl, 5-cyclobutyl-pyrazin-2-yl, 5-ethoxy-pyrazin-2-yl,5-trifluoromethyl-pyrazin-2-yl, 5-cyano-pyridin-3-yl,5-cyclopropylmethyl-pyrazin-2-yl, 5-pentafluoroethyl-pyrazin-2-yl,5-heptafluoropropyl-pyrazin-2-yl, 5-chloro-4-methyl-pyridin-2-yl,5-chloro-4-trifluoromethyl-pyridin-2-yl, 4-bromo-pyridin-2-yl,4-chloro-pyridin-2-yl, 4-fluoro-pyridin-2-yl, 4-oxy-pyrazin-2-yl,4-cyclopropyl-pyridin-2-yl, 4-cyano-pyridin-2-yl,4-methanesulfonyl-pyridin-2-yl, 4-methoxy-pyridin-2-yl, andpiperidin-4-yl.

In some embodiments, R⁷ is 2,4-difluoro-phenyl. In some embodiments, R⁷is 5-bromo-pyridin-2-yl. In some embodiments, R⁷ is 4-cyano-phenyl. Insome embodiments, R⁷ is pyridin-3-yl. In some embodiments, R⁷ ispyridin-2-yl. In some embodiments, R⁷ is 5-thiazol-2-yl-pyridin-2-yl. Insome embodiments, R⁷ is 5-trifluoromethyl-pyridin-2-yl. In someembodiments, R⁷ is 5-o-tolyl-pyridin-2-yl. In some embodiments, R⁷ is5-dimethylamino-pyrazin-2-yl. In some embodiments, R⁷ is2,4-dichloro-phenyl. In some embodiments, R⁷ is5-isopropyl-pyridin-2-yl. In some embodiments, R⁷ is5-methyl-pyridin-2-yl. In some embodiments, R⁷ is5-(4-methoxy-phenyl)-pyridin-2-yl. In some embodiments, R⁷ is2-fluoro-4-methanesulfonyl-phenyl. In some embodiments, R⁷ is2-fluoro-phenyl. In some embodiments, R⁷ is 5-chloro-pyridin-2-yl. Insome embodiments, R⁷ is 5-bromo-pyridin-3-yl. In some embodiments, R⁷ istert-butyl. In some embodiments, R⁷ is 2-methoxy-pyridin-4-yl. In someembodiments, R⁷ is 2,2-dimethyl-propyl. In some embodiments, R⁷ istetrahydro-pyran-4-ylmethyl. In some embodiments, R⁷ is phenyl. In someembodiments, R⁷ is 4-trifluoromethyl-pyridin-2-yl. In some embodiments,R⁷ is 6-chloro-pyrazin-2-yl. In some embodiments, R⁷ is1-oxo-hexahydro-1λ⁴-thiopyran-4-yl. In some embodiments, R⁷ is5-morpholin-4-yl-pyridin-2-yl. In some embodiments, R⁷ is6-bromo-pyridin-3-yl. In some embodiments, R⁷ is 5-methoxy-pyridin-2-yl.In some embodiments, R⁷ is 5,6-difluoro-pyridin-3-yl. In someembodiments, R⁷ is 6-methoxy-pyridazin-3-yl. In some embodiments, R⁷ is2-chloro-pyridin-4-yl. In some embodiments, R⁷ is5-cyclopropyl-pyrazin-2-yl. In some embodiments, R⁷ is1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl. In some embodiments, R⁷ is1-benzyl-piperidin-4-yl. In some embodiments, R⁷ is6-cyano-pyrazin-2-yl. In some embodiments, R⁷ is2-hydroxy-2-methyl-propyl. In some embodiments, R⁷ is 4-fluoro-phenyl.In some embodiments, R⁷ is 5-ethyl-pyridin-2-yl. In some embodiments, R⁷is isopropyl. In some embodiments, R⁷ is 5-phenyl-pyridin-2-yl. In someembodiments, R⁷ is pyridin-4-yl. In some embodiments, R⁷ is2,5-difluoro-phenyl. In some embodiments, R⁷ is 3-fluoro-phenyl. In someembodiments, R⁷ is pyrimidin-4-yl. In some embodiments, R⁷ is2-(tetrahydro-pyran-4-yl)-ethyl. In some embodiments, R⁷ is3,5-difluoro-pyridin-2-yl. In some embodiments, R⁷ is pyrazin-2-yl. Insome embodiments, R⁷ is tetrahydro-thiopyran-4-yl. In some embodiments,R⁷ is 5-p-tolyl-pyridin-2-yl. In some embodiments, R⁷ is4-methoxy-phenyl. In some embodiments, R⁷ is 2-morpholin-4-yl-ethyl. Insome embodiments, R⁷ is 5-cyano-pyridin-2-yl. In some embodiments, R⁷ is5-cyano-pyrazin-2-yl. In some embodiments, R⁷ is6′-methyl-[3,3′]bipyridinyl-6-yl. In some embodiments, R⁷ is6-chloro-pyridazin-3-yl. In some embodiments, R⁷ is5-fluoro-pyridin-2-yl. In some embodiments, R⁷ is 5-ethyl-pyrazin-2-yl.In some embodiments, R⁷ is 6-methoxy-pyrazin-2-yl. In some embodiments,R⁷ is 5-dimethylamino-pyridin-2-yl. In some embodiments, R⁷ is1-(4-fluoro-phenyl)-1-methyl-ethyl. In some embodiments, R⁷ is5-pyrimidin-5-yl-pyridin-2-yl. In some embodiments, R⁷ is4-methyl-pyridin-2-yl. In some embodiments, R⁷ is5-methoxy-pyrazin-2-yl. In some embodiments, R⁷ is5-propyl-pyridin-2-yl. In some embodiments, R⁷ is5-m-tolyl-pyridin-2-yl. In some embodiments, R⁷ is5-hydroxy-pyrazin-2-yl. In some embodiments, R⁷ iscyclopropyl-pyridin-2-yl. In some embodiments, R⁷ is2,6-difluoro-phenyl. In some embodiments, R⁷ is 3-fluoro-pyridin-4-yl.In some embodiments, R⁷ is 5-isopropyl-pyrazin-2-yl. In someembodiments, R⁷ is 5-bromo-pyrazin-2-yl. In some embodiments, R⁷ is5-cyclopentyl-pyridin-2-yl. In some embodiments, R⁷ is o-tolyl. In someembodiments, R⁷ is 4-fluoro-benzyl. In some embodiments, R⁷ is3-methyl-pyridin-2-yl. In some embodiments, R⁷ is6-methyl-4-trifluoromethyl-pyridin-2-yl. In some embodiments, R⁷ is6-dimethylamino-pyrazin-2-yl. In some embodiments, R⁷ is1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl. In some embodiments, R⁷ is5-(4-fluoro-phenyl)-pyridin-2-yl. In some embodiments, R⁷ is5-cyclopropyl-pyridin-2-yl. In some embodiments, R⁷ is6-ethyl-pyrazin-2-yl. In some embodiments, R⁷ is5-methylamino-pyrazin-2-yl. In some embodiments, R⁷ is dichloro-phenyl.In some embodiments, R⁷ is 5-methyl-pyrazin-2-yl. In some embodiments,R⁷ is 3-fluoro-pyridin-2-yl. In some embodiments, R⁷ is5-cyclobutyl-pyrazin-2-yl. In some embodiments, R⁷ is5-ethoxy-pyrazin-2-yl. In some embodiments, R⁷ is5-trifluoromethyl-pyrazin-2-yl. In some embodiments, R⁷ is5-cyano-pyridin-3-yl. In some embodiments, R⁷ is5-cyclopropylmethyl-pyrazin-2-yl. In some embodiments, R⁷ is5-pentafluoroethyl-pyrazin-2-yl. In some embodiments, R⁷ is5-heptafluoropropyl-pyrazin-2-yl. In some embodiments, R⁷ is5-chloro-4-methyl-pyridin-2-yl. In some embodiments, R⁷ is5-chloro-4-trifluoromethyl-pyridin-2-yl. In some embodiments, R⁷ is4-bromo-pyridin-2-yl. In some embodiments, R⁷ is 4-chloro-pyridin-2-yl.In some embodiments, R⁷ is 4-fluoro-pyridin-2-yl. In some embodiments,R⁷ is 4-oxy-pyrazin-2-yl. In some embodiments, R⁷ is4-cyclopropyl-pyridin-2-yl. In some embodiments, R⁷ is4-cyano-pyridin-2-yl. In some embodiments, R⁷ is4-methanesulfonyl-pyridin-2-yl. In some embodiments, R⁷ is4-methoxy-pyridin-2-yl. In some embodiments, R⁷ is piperidin-4-yl. Insome embodiments, R⁷ is tetrahydro-pyran-4-yl. In some embodiments, R⁷is 3-methyl-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl. In some embodiments,R⁷ is 5-chloro-3-fluoro-pyridin-2-yl. In some embodiments, R⁷ is3-fluoro-5-methoxy-pyridin-2-yl. In some embodiments, R⁷ is2-chloro-4-fluoro-phenyl. In some embodiments, R⁷ is6-fluoro-pyridin-3-yl. In some embodiments, R⁷ is 6-cyano-pyridin-3-yl.In some embodiments, R⁷ is 3-hydroxy-3-methyl-butyl. In someembodiments, R⁷ is 4-iodo-pyridin-2-yl. In some embodiments, R⁷ is1-oxy-pyridin-3-yl. In some embodiments, R⁷ is4-tert-butylcarbamoyl-pyridin-2-yl. In some embodiments, R⁷ is4-hydroxy-pyridin-2-yl.

The Group R⁸:

In some embodiments, R⁸ is —R¹⁴—R¹⁵—R¹⁶—R¹⁷.

In some embodiments, R⁸ is selected from:1-hydroxymethyl-2,2-dimethyl-propyl, 2-hydroxy-1,1-dimethyl-ethyl,1-hydroxymethyl-cyclopropyl, 2-hydroxy-indan-1-yl,1-hydroxymethyl-cyclobutyl, tert-butyl, 2-hydroxy-1-phenyl-ethyl,2-hydroxy-1-hydroxymethyl-1-methyl-ethyl, tert-butylamino,2,2,2-trifluoro-1,1-dimethyl-ethyl,2-methyl-1-(phosphonooxy)propan-2-yl, 1-methyl-cyclobutyl,1-hydroxymethyl-2-methyl-propyl, cyano-dimethyl-methyl,2,2-dimethyl-1-(methylcarbamoyl)-propyl,3,3-dimethyl-1-(phosphonooxy)butan-2-yl,2-hydroxy-1-tetrahydro-pyran-4-yl-ethyl, 1,2-dimethyl-propyl,1-pyridin-2-yl-cyclobutyl, 2-(methylamino)-2-oxo-1-phenylethyl,2,2-dimethyl-1-pyridin-2-yl-propyl,1-methoxy-3,3-dimethyl-1-oxobutan-2-yl,1-(2-amino-3-methylbutanoyloxy)-3-methylbutan-2-yl,1-(4-carboxybutanoyloxy)-3-methylbutan-2-yl,3,3,3-trifluoro-1-hydroxymethyl-propyl, 2-fluoro-1,1-dimethyl-ethyl,2-fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl,1-fluoromethyl-2,2-dimethyl-propyl, 1-fluoromethyl-cyclobutyl,1-trifluoromethyl-cyclopropyl, and 1-trifluoromethyl-cyclobutyl.

In some embodiments, R⁸ is selected from: H,2-methyl-2-morpholin-4-yl-propyl, 1-hydroxymethyl-2,2-dimethyl-propyl,2-(tert-butoxycarbonylamino)cyclohexyl, 1-phenyl-cyclopropyl,5-trifluoromethyl-pyridin-2-yl, 1-methyl-1-phenyl-ethyl,1-(2-methoxy-ethyl)-pyrrolidin-3-ylmethyl,1-(methoxycarbonyl)cyclopropyl, tetrahydro-pyran-4-ylmethyl,1-(tert-butoxycarbonyl)piperidin-4-yl, 1-(4-fluoro-phenyl)-cyclopropyl,6-methyl-pyridin-3-ylmethyl, 2-hydroxy-1-phenyl-ethyl,1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl, 2-hydroxy-1,1-dimethyl-ethyl,2-(5-hydroxy-1H-indol-3-yl)-ethyl, 1-hydroxymethyl-cyclopropyl,3-chloro-5-methyl-pyridin-2-yl, 6-fluoro-pyridin-3-yl,1-(3-fluoro-phenyl)-cyclobutyl, 2-methyl-pyridin-3-yl,2-hydroxy-1-(tetrahydro-furan-3-yl)-ethyl, 2-(pyridin-3-yloxy)-propyl,carbamoyl-phenyl-methyl, 5-fluoro-2-methoxy-phenyl, 2-methoxy-ethyl,2,3-dihydroxy-propyl, 1-(tert-butoxycarbonyl)pyrrolidin-3-yl,2-oxo-2-phenyl-ethyl, 1-(3,3,3-trifluoro-propyl)-azetidin-3-yl,2-hydroxy-1-pyridin-2-yl-ethyl, 3-hydroxy-pyridin-4-yl,1-methyl-1-pyridin-4-yl-ethyl, 1-hydroxymethyl-2-3H-imidazol-4-yl-ethyl,4-hydroxy-3-methoxy-benzyl, 5-fluoro-2-oxo-2,3-dihydro-pyrimidin-4-yl,1-(4-fluoro-phenyl)-3-hydroxy-propyl, 1-pyridin-4-yl-cyclopropyl,2-hydroxy-1-pyridin-3-yl-ethyl,1,1-dimethyl-2-(4-methyl-piperidin-1-yl)-ethyl, 6-cyano-pyridin-3-yl,5-fluoro-pyridin-2-yl, 2,5-dimethyl-benzyl, 1-isopropyl-piperidin-4-yl,2-methoxy-1-methoxymethyl-ethyl, 2,3-dimethyl-benzyl,1-pyridin-2-yl-ethyl, 6-chloro-pyridin-3-ylmethyl,3-methyl-pyridin-2-yl, 2-hydroxy-indan-1-yl, 1-hydroxymethyl-cyclobutyl,2-(4-chloro-phenyl)-1,1-dimethyl-ethyl, 3-hydroxy-pyridin-2-ylmethyl,3-methyl-pyridin-4-yl, 5-tert-butyl-isoxazol-3-yl,1-(6-methoxy-pyridin-3-yl)-1-methyl-ethyl, 1H-benzoimidazol-2-yl,tert-butyl, 4-phenyl-thiazol-2-yl, 1-(2-fluoro-phenyl)-cyclobutyl,2,4-dimethoxy-benzyl, 5-bromo-3-methyl-pyridin-2-yl,4-benzyl-morpholin-2-ylmethyl, 6-trifluoromethyl-pyridin-3-ylmethyl,tetrahydro-furan-3-yl, pyridin-3-ylmethyl, pyrazin-2-yl, piperidin-4-yl,1-(6-hydroxy-pyridin-3-yl)-1-methyl-ethyl,1-methyl-1-pyridin-2-yl-ethyl, 1-hydroxymethyl-cyclopentyl,1-aza-bicyclo[2.2.2]oct-3-yl, 2-hydroxy-cyclopentyl,2-hydroxy-1-(hydroxymethyl)-propyl,1-(tert-butoxycarbonyl)piperidin-4-yl)methyl, 3,5-dimethoxy-phenyl,6-fluoro-4H-benzo[1,3]dioxin-8-ylmethyl, 4,6-dimethyl-pyridin-2-yl,1,1-dimethyl-2-morpholin-4-yl-ethyl, 2-hydroxy-cyclohexylmethyl,1-(4-methoxy-phenyl)-cyclopropyl, 1-ethyl-pyrrolidin-2-ylmethyl,indan-1-yl, pyrimidin-4-yl, 2-fluoro-4-methanesulfonyl-phenyl,6-hydroxy-pyridin-2-yl, cyclobutyl, 1-(3-methoxy-phenyl)-cyclopropyl,1-(3,3,3-trifluoro-propyl)-pyrrolidin-3-yl, 2-hydroxy-pyridin-3-yl,4-difluoromethoxy-benzyl, 1-piperidin-1-yl-cyclopentylmethyl,3-hydroxy-3-methyl-butyl, 1-(4-fluoro-phenyl)-cyclobutyl,4-methoxy-benzyl, pyridin-2-yl, 2-hydroxy-2-phenyl-ethyl,2-hydroxymethyl-2,3-dihydro-indol-1-yl, 3-hydroxy-pyridin-2-yl,4-dimethylamino-tetrahydro-pyran-4-ylmethyl, 2-(4-fluoro-phenyl)-ethyl,1-(2-methoxy-ethyl)-piperidin-4-ylmethyl, 2-morpholin-4-yl-ethyl,1-(tert-butoxycarbonyl)-4-carboxypiperidin-4-yl, quinolin-3-yl,1-morpholin-4-ylmethyl-cyclopentyl, 1,4-dimethyl-1H-pyrrol-2-ylmethyl,2-hydroxy-2-pyridin-2-yl-ethyl, pyridin-3-yl, 2-dimethylamino-benzyl,tetrahydro-thiopyran-4-yl, 1-m-tolyl-cyclopropyl,1-(2-methoxy-ethyl)-piperidin-3-yl, 5-methoxy-pyridin-2-ylmethyl,2-hydroxy-1-pyridin-4-yl-ethyl, 4-methyl-pyridin-2-yl,4-carboxy-2-fluorophenyl, 6-methanesulfonyl-pyridin-3-yl,1-o-tolyl-cyclobutyl, 1,1-dimethyl-2-pyrrolidin-1-yl-ethyl,2,6-dimethoxy-pyridin-3-yl, pyridin-2-yl,4-hydroxymethyl-tetrahydro-pyran-4-yl, 2-(1H-imidazol-4-yl)-ethyl,3-fluoro-pyridin-4-yl, 1-carbamoyl-2-phenyl-ethyl, oxazol-4-ylmethyl,6-methoxy-pyrimidin-4-yl, 1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl,1-methoxy-1-oxo-3-phenylpropan-2-yl,1-(2-methoxy-ethyl)-pyrrolidin-3-yl, 1-(6-methyl-pyridin-2-yl)-ethyl,2-hydroxy-1-(4-hydroxy-phenyl)-ethyl, 2-methoxy-pyridin-4-yl,1-pyridin-2-yl-cyclopropyl, 1-(tert-butoxycarbonyl)piperidin-3-yl,3-methyl-pyridin-2-ylmethyl, 3-fluoro-pyridin-2-yl,1-pyridin-4-yl-cyclobutyl, 2-carboxy-1-(pyridin-3-yl)ethyl,2-hydroxy-1-methyl-ethyl, 1-(methoxycarbonyl)cyclohexyl,3-hydroxymethyl-pyridin-4-yl, 2-hydroxy-1-phenyl-ethyl,3-dimethylamino-tetrahydro-thiophen-3-ylmethyl, tetrahydro-pyran-4-yl,5-chloro-pyridin-2-yl, 1-carbamoyl-cyclobutyl, 5-fluoro-2-methyl-benzyl,2-morpholin-4-yl-2-pyridin-3-yl-ethyl, 1-(3-methoxy-phenyl)-cyclobutyl,5-methyl-pyridin-2-yl, 1-(tetrahydro-furan-2-yl)methyl,1-dimethylaminomethyl-cyclopentyl, 2-(4-fluoro-phenyl)-1-methyl-ethyl,benzothiazol-2-yl, 1-(2-fluoro-phenyl)-cyclopropyl,1-(2-methoxy-ethyl)-piperidin-4-yl, 2-hydroxy-1-pyridin-4-yl-ethyl,1-(3,3,3-trifluoro-propyl)-azetidin-3-ylmethyl,6-pyrrolidin-1-yl-pyridin-2-ylmethyl,1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl, 2,3-dimethoxy-benzyl,3-cyano-5-methyl-pyridin-2-yl, 2,3-dihydro-benzofuran-3-yl,1-hydroxymethyl-cyclohexyl, 2,5-difluoro-benzyl, 4-dimethylamino-benzyl,4-hydroxy-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl,4-trifluoromethyl-pyridin-2-yl, 5-methyl-thiazol-2-yl,6-trifluoromethyl-pyridin-3-yl, 5-hydroxy-1H-pyrazol-3-yl,2-thiomorpholin-4-yl-ethyl, benzo[1,3]dioxol-5-ylmethyl,2-amino-cyclohexyl,3-dimethylamino-1-oxo-tetrahydro-1λ⁴-thiophen-3-ylmethyl,4-methyl-morpholin-2-ylmethyl, 1-(2-methoxy-phenyl)-cyclopropyl,2-carboxy-1-(4-fluorophenyl)propan-2-yl, pyridin-2-ylmethyl,pyridazin-3-yl, 4-pyridin-2-yl-thiazol-2-yl,1-(3,3,3-trifluoro-propyl)-piperidin-4-ylmethyl,6-chloro-2-methyl-pyridin-3-yl, 6-hydroxy-pyridin-3-yl,3-trifluoromethoxy-benzyl, 1-morpholin-4-yl-cyclopentylmethyl,1-pyridin-2-yl-cyclobutylmethyl, indan-1-ylamide,2-hydroxy-1-hydroxymethyl-1-methyl-ethyl, 5-hydroxymethyl-pyridin-2-yl,5-fluoro-1-oxy-pyridin-2-yl, 6-methoxy-pyridin-2-yl,1-methyl-1-pyridin-3-yl-ethyl, 6-methyl-pyridin-3-yl,2-hydroxy-1-hydroxymethyl-propyl, 2-chloro-pyridin-3-yl,3-methyl-3H-imidazol-4-ylmethyl, 6-fluoro-pyridin-2-yl,3-dimethylamino-benzyl, 6-morpholin-4-yl-pyridin-3-yl,1-o-tolyl-cyclopropyl, 1-(3,3,3-trifluoro-propyl)-piperidin-3-yl,6-methanesulfonyl-4-methyl-pyridin-3-yl, 2-methyl-quinolin-4-yl,1-(3,3,3-trifluoro-propyl)-pyrrolidin-3-ylmethyl, benzooxazol-2-yl,1-methyl-piperidin-4-ylmethyl,2-(2,6-dimethyl-morpholin-4-yl)-2-methyl-propyl,1-methyl-piperidin-2-ylmethyl, pyridin-4-ylmethyl,4-hydroxymethyl-pyridin-2-yl,5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl,6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl,1-(5-methyl-pyridin-2-yl)-ethyl, 2-fluoro-pyridin-3-yl, morpholin-4-yl,2-hydroxy-2-pyridin-4-yl-ethyl, pyridin-4-yl, 4-hydroxy-pyridin-2-yl,3-methoxy-benzyl, 1-oxy-pyridin-2-yl, 1-ethyl-propyl,6-carboxypyridin-2-yl, 1,2,2,6,6-pentamethyl-piperidin-4-yl,6-methoxy-pyridin-3-yl, cyclopentyl, morpholin-2-ylmethyl,1-(tert-butoxycarbonyl)azetidin-3-yl)methyl,2-dimethylamino-2-pyridin-3-yl-ethyl, 1-(4-methoxy-phenyl)-cyclobutyl,3-hydroxy-benzyl, tetrahydro-furan-2-ylmethyl,4-(tert-butoxycarbonyl)morpholin-2-ylmethyl,1-(3-fluoro-phenyl)-cyclopropyl, 2-o-tolyl-ethyl,3-hydroxymethyl-1-isobutyl-pyrrolidin-3-yl,1-(2-methoxy-ethyl)-azetidin-3-yl, 6-morpholin-4-yl-pyridin-2-ylmethyl,1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-ylmethyl,2-(4-fluoro-phenoxy)-ethyl, 2,6-dimethyl-pyrimidin-4-yl,1-hydroxymethyl-2-(3H-imidazol-4-yl)-ethyl, 4-methanesulfonyl-benzyl,1-pyridin-3-yl-cyclopropyl, 9-methyl-9-aza-bicyclo[3.3.1]non-1-yl,2,6-dimethyl-pyridin-3-yl, 4-hydroxy-benzyl, 2-oxo-2-phenyl-ethyl),1-methyl-1H-pyrazol-3-ylmethyl, pyrimidin-2-yl, 5-methyl-pyrazin-2-yl,1-(2-methoxy-pyridin-3-yl)-1-methyl-ethyl,6-methanesulfonyl-2-methyl-pyridin-3-yl, 2-hydroxy-benzyl,6-bromo-2-methyl-pyridin-3-yl, 2-methoxy-pyridin-3-yl,1-(4-chloro-phenyl)-cyclobutyl, 2-(pyridine-2-sulfonyl)-ethyl,1-pyridin-2-yl-cyclopropylmethyl,1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl, benzyl,3,5-dimethyl-pyrazin-2-yl, 1-(2-hydroxy-pyridin-3-yl)-1-methyl-ethyl,1-(ethoxycarbonyl)cyclobutyl,1-(tert-butoxycarbonyl)pyrrolidin-3-ylmethyl, quinolin-4-ylmethyl,2-(4-fluoro-phenyl)-1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethyl,2-morpholin-4-yl-pyridin-3-yl, 6-methyl-pyridin-2-yl,3-difluoromethoxy-benzyl, 4-hydroxy-1-methyl-piperidin-4-ylmethyl,1-(2,5-dimethylpyrrolidine-1-carbonyl)cyclopentyl, 2-methoxy-benzyl,6-methyl-pyridin-2-ylmethyl, 3-chloro-pyridin-4-yl,2-carboxypropan-2-yl, 6-chloro-pyridin-3-yl,2-hydroxy-2-pyridin-3-yl-ethyl, 1-p-tolyl-cyclopropyl,1-(3,3,3-trifluoro-propyl)-piperidin-4-yl, 4-methoxy-pyridin-2-yl,3-azepan-1-yl-2,2-dimethyl-propyl, 1-(tert-butoxycarbonyl)azetidin-3-yl,5-methyl-pyrazin-2-ylmethyl, 1-oxo-hexahydro-1λ⁴-thiopyran-4-yl,2-(2-chloro-phenyl)-ethyl,3-chloro-5-trifluoromethyl-pyridin-2-ylmethyl,2-hydroxy-1-hydroxymethyl-ethyl,(1-methyl-pyrrolidin-2-yl)-pyridin-2-yl, 5-fluoro-2-hydroxy-phenyl,methyl, 4-(methoxycarbonyl)-1-methylpiperidin-4-yl,4-hydroxymethyl-1-methyl-piperidin-4-yl,2-(2-hydroxymethyl-pyrrolidin-1-yl)-ethyl, 1-phenyl-cyclohexyl,3-methyl-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl, 1-cyano-cyclohexyl,1-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl, 2-cyanopropan-2-yl,3-methyl-1-phenylureido, 1-carbamoyl-2,2-dimethyl-propyl,tert-butylamino, 2,2,2-trifluoro-1,1-dimethyl-ethyl,2,2-dimethyl-1-methylcarbamoyl-propyl, 1-cyclopropyl-ethyl, amino,N-tert-butylmethylsulfonamido, 1,1-dimethyl-prop-2-ynyl,2-methyl-1-(phosphonooxy)propan-2-yl, 1-tert-butyl-3-methylureido,4-cyano-tetrahydro-pyran-4-yl, 1-methyl-cyclobutyl,1-hydroxymethyl-2-methyl-propyl, cyclobutylamino, 1-cyano-cyclopentyl,cyano-dimethyl-methyl, 2,2-dimethyl-1-(methylcarbamoyl)-propyl,phenylamino, 1-hydroxymethyl-propyl,1-methyl-1-(1H-tetrazol-5-yl)-ethyl,3,3-dimethyl-1-(phosphonooxy)butan-2-yl),2-hydroxy-1-tetrahydro-pyran-4-yl-ethyl, 1,2-dimethyl-propyl,1-pyridin-2-yl-cyclobutyl, 1-hydroxymethyl-2-phenyl-ethyl,4-methylcarbamoyl-tetrahydro-pyran-4-yl,1-methyl-1-methylcarbamoyl-ethyl,2,2-dimethyl-1-morpholin-4-ylmethyl-propyl,1-methylcarbamoyl-cyclopent-3-enyl,2-methoxy-2-oxo-1-(pyridin-2-yl)ethyl,methylcarbamoyl-pyridin-2-yl-methyl, 1-methylcarbamoyl-cyclopentyl,1-(tert-butylcarbamoyl)-2,2-dimethyl-propyl,2,2-dimethyl-1-(pyridin-2-ylcarbamoyl)-propyl,1-(pyridin-2-ylcarbamoyl)-cyclobutyl, 1-methylcarbamoyl-cyclobutyl,2-(methylamino)-2-oxo-1-phenylethyl, pyrrolidin-1-yl, piperidin-1-yl,2,6-dimethyl-piperidin-1-yl, 1-cyclopropylcarbamoyl-2,2-dimethyl-propyl,2,2-dimethyl-1-(2,2,2-trifluoro-ethylcarbamoyl)-propyl,1-ethylcarbamoyl-2,2-dimethyl-propyl,2-hydroxy-1-(tetrahydro-pyran-4-yl)-ethyl,N-cyclobutylmethylsulfonamido, N-phenylmethylsulfonamido,1-cyclopropyl-2-hydroxy-ethyl, 1,2,2-trimethyl-propyl,2-oxo-1-(pyridin-2-yl)-2-(2,2,2-trifluoroethylamino)ethyl,2,2-dimethyl-1-pyridin-2-yl-propyl,1-methoxy-3,3-dimethyl-1-oxobutan-2-yl, 1-carboxy-2,2-dimethylpropyl,1-(hydroxy-methyl-carbamoyl)-2,2-dimethyl-propyl,1-dimethylcarbamoyl-2,2-dimethyl-propyl,1-(azetidine-1-carbonyl)-2,2-dimethyl-propyl,1-methoxycarbamoyl-2,2-dimethyl-propyl,1-(methoxy-methyl-carbamoyl)-2,2-dimethyl-propyl,1-tert-butoxycarbamoyl-2,2-dimethyl-propyl,2,2-dimethyl-1-pyridin-2-yl-propyl,(1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl)amino,1-hydroxycarbamoyl-2,2-dimethyl-propyl, 1-hydroxymethyl-2-methyl-butyl,1-(2-hydroxy-ethylcarbamoyl)-2,2-dimethyl-propyl,1,1-bis-hydroxymethyl-propyl,1-(5-fluoro-pyridin-2-yl)-2,2-dimethyl-propyl,4-hydroxymethyl-tetrahydro-2H-pyran-4-yl,1-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)-2-methylpropan-2-yl,1-(2-amino-3-methylbutanoyloxy)-3-methylbutan-2-yl,1-(2-amino-3-methylbutanoyloxy)-2-methylpropan-2-yl,2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-ethyl,1-(4-carboxybutanoyloxy)-2-methylpropan-2-yl,1-(4-carboxybutanoyloxy)-3-methylbutan-2-yl,1-(4-carboxybutanoyloxy)-3,3-dimethylbutan-2-yl,1-(2-amino-3-methylbutanoyloxy)-3,3-dimethylbutan-2-yl,2-(2-amino-3-methylbutanoyloxy)-1-(tetrahydro-2H-pyran-4-yl)ethyl,3,3,3-trifluoro-1-hydroxymethyl-propyl,3-fluoro-1-methoxy-3-methyl-1-oxobutan-2-yl,1-ethoxy-4,4,4-trifluoro-1-oxo-3-(trifluoromethyl)butan-2-yl,2-fluoro-1-hydroxymethyl-2-methyl-propyl,1-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)-3,3-dimethylbutan-2-yl,4,4,4-trifluoro-1-methoxy-1-oxobutan-2-yl, 2-fluoro-1,1-dimethyl-ethyl,3-fluoro-2-(fluoromethyl)-1-methoxy-1-oxopropan-2-yl,2-fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl,3-hydroxy-1-methoxy-2-methyl-1-oxopropan-2-yl,2-carboxy-1-hydroxypropan-2-yl, 2,2,2-trifluoroethylamino,1-fluoromethyl-2-methyl-propyl, 1-fluoromethyl-2,2-dimethyl-propyl,3-methyl-oxetan-3-yl, 1-fluoromethyl-cyclobutyl,1,1-bis-hydroxymethyl-2-methyl-propyl, 1-trifluoromethyl-cyclopropyl,1-methyl-cyclopropyl, and 1-trifluoromethyl-cyclobutyl.

In some embodiments, R⁸ is selected from: H,2-methyl-2-morpholin-4-yl-propyl, 1-hydroxymethyl-2,2-dimethyl-propyl,2-(tert-butoxycarbonylamino)cyclohexyl, 1-phenyl-cyclopropyl,5-trifluoromethyl-pyridin-2-yl, 1-methyl-1-phenyl-ethyl,1-(2-methoxy-ethyl)-pyrrolidin-3-ylmethyl,1-(methoxycarbonyl)cyclopropyl, tetrahydro-pyran-4-ylmethyl,1-(tert-butoxycarbonyl)piperidin-4-yl, 1-(4-fluoro-phenyl)-cyclopropyl,6-methyl-pyridin-3-ylmethyl, 2-hydroxy-1-phenyl-ethyl,1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl, 2-hydroxy-1,1-dimethyl-ethyl,2-(5-hydroxy-1H-indol-3-yl)-ethyl, 1-hydroxymethyl-cyclopropyl,3-chloro-5-methyl-pyridin-2-yl, 6-fluoro-pyridin-3-yl,1-(3-fluoro-phenyl)-cyclobutyl, 2-methyl-pyridin-3-yl,2-hydroxy-1-(tetrahydro-furan-3-yl)-ethyl, 2-(pyridin-3-yloxy)-propyl,carbamoyl-phenyl-methyl, 5-fluoro-2-methoxy-phenyl, 2-methoxy-ethyl,2,3-dihydroxy-propyl, 1-(tert-butoxycarbonyl)pyrrolidin-3-yl,2-oxo-2-phenyl-ethyl, 1-(3,3,3-trifluoro-propyl)-azetidin-3-yl,2-hydroxy-1-pyridin-2-yl-ethyl, 3-hydroxy-pyridin-4-yl,1-methyl-1-pyridin-4-yl-ethyl, 1-hydroxymethyl-2-3H-imidazol-4-yl-ethyl,4-hydroxy-3-methoxy-benzyl, 5-fluoro-2-oxo-2,3-dihydro-pyrimidin-4-yl,1-(4-fluoro-phenyl)-3-hydroxy-propyl, 1-pyridin-4-yl-cyclopropyl,2-hydroxy-1-pyridin-3-yl-ethyl,1,1-dimethyl-2-(4-methyl-piperidin-1-yl)-ethyl, 6-cyano-pyridin-3-yl,5-fluoro-pyridin-2-yl, 2,5-dimethyl-benzyl, 1-isopropyl-piperidin-4-yl,2-methoxy-1-methoxymethyl-ethyl, 2,3-dimethyl-benzyl,1-pyridin-2-yl-ethyl, 6-chloro-pyridin-3-ylmethyl,3-methyl-pyridin-2-yl, 2-hydroxy-indan-1-yl, 1-hydroxymethyl-cyclobutyl,2-(4-chloro-phenyl)-1,1-dimethyl-ethyl, 3-hydroxy-pyridin-2-ylmethyl,3-methyl-pyridin-4-yl, 5-tert-butyl-isoxazol-3-yl,1-(6-methoxy-pyridin-3-yl)-1-methyl-ethyl, 1H-benzoimidazol-2-yl,tert-butyl, 4-phenyl-thiazol-2-yl, 1-(2-fluoro-phenyl)-cyclobutyl,2,4-dimethoxy-benzyl, 5-bromo-3-methyl-pyridin-2-yl,4-benzyl-morpholin-2-ylmethyl, 6-trifluoromethyl-pyridin-3-ylmethyl,tetrahydro-furan-3-yl, pyridin-3-ylmethyl, pyrazin-2-yl, piperidin-4-yl,1-(6-hydroxy-pyridin-3-yl)-1-methyl-ethyl,1-methyl-1-pyridin-2-yl-ethyl, 1-hydroxymethyl-cyclopentyl,1-aza-bicyclo[2.2.2]oct-3-yl, 2-hydroxy-cyclopentyl,2-hydroxy-1-(hydroxymethyl)-propyl,1-(tert-butoxycarbonyl)piperidin-4-yl)methyl, 3,5-dimethoxy-phenyl,6-fluoro-4H-benzo[1,3]dioxin-8-ylmethyl, 4,6-dimethyl-pyridin-2-yl,1,1-dimethyl-2-morpholin-4-yl-ethyl, 2-hydroxy-cyclohexylmethyl,1-(4-methoxy-phenyl)-cyclopropyl, 1-ethyl-pyrrolidin-2-ylmethyl,indan-1-yl, pyrimidin-4-yl, 2-fluoro-4-methanesulfonyl-phenyl,6-hydroxy-pyridin-2-yl, cyclobutyl, 1-(3-methoxy-phenyl)-cyclopropyl,1-(3,3,3-trifluoro-propyl)-pyrrolidin-3-yl, 2-hydroxy-pyridin-3-yl,4-difluoromethoxy-benzyl, 1-piperidin-1-yl-cyclopentylmethyl,3-hydroxy-3-methyl-butyl, 1-(4-fluoro-phenyl)-cyclobutyl,4-methoxy-benzyl, pyridin-2-yl, 2-hydroxy-2-phenyl-ethyl,2-hydroxymethyl-2,3-dihydro-indol-1-yl, 3-hydroxy-pyridin-2-yl,4-dimethylamino-tetrahydro-pyran-4-ylmethyl, 2-(4-fluoro-phenyl)-ethyl,1-(2-methoxy-ethyl)-piperidin-4-ylmethyl, 2-morpholin-4-yl-ethyl,1-(tert-butoxycarbonyl)-4-carboxypiperidin-4-yl, quinolin-3-yl,1-morpholin-4-ylmethyl-cyclopentyl, 1,4-dimethyl-1H-pyrrol-2-ylmethyl,2-hydroxy-2-pyridin-2-yl-ethyl, pyridin-3-yl, 2-dimethylamino-benzyl,tetrahydro-thiopyran-4-yl, 1-m-tolyl-cyclopropyl,1-(2-methoxy-ethyl)-piperidin-3-yl, 5-methoxy-pyridin-2-ylmethyl,2-hydroxy-1-pyridin-4-yl-ethyl, 4-methyl-pyridin-2-yl,4-carboxy-2-fluorophenyl, 6-methanesulfonyl-pyridin-3-yl,1-o-tolyl-cyclobutyl, 1,1-dimethyl-2-pyrrolidin-1-yl-ethyl,2,6-dimethoxy-pyridin-3-yl, pyridin-2-yl,4-hydroxymethyl-tetrahydro-pyran-4-yl, 2-(1H-imidazol-4-yl)-ethyl,3-fluoro-pyridin-4-yl, 1-carbamoyl-2-phenyl-ethyl, oxazol-4-ylmethyl,6-methoxy-pyrimidin-4-yl, 1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl,1-methoxy-1-oxo-3-phenylpropan-2-yl,1-(2-methoxy-ethyl)-pyrrolidin-3-yl, 1-(6-methyl-pyridin-2-yl)-ethyl,2-hydroxy-1-(4-hydroxy-phenyl)-ethyl, 2-methoxy-pyridin-4-yl,1-pyridin-2-yl-cyclopropyl, 1-(tert-butoxycarbonyl)piperidin-3-yl,3-methyl-pyridin-2-ylmethyl, 3-fluoro-pyridin-2-yl,1-pyridin-4-yl-cyclobutyl, 2-carboxy-1-(pyridin-3-yl)ethyl,2-hydroxy-1-methyl-ethyl, 1-(methoxycarbonyl)cyclohexyl,3-hydroxymethyl-pyridin-4-yl, 2-hydroxy-1-phenyl-ethyl,3-dimethylamino-tetrahydro-thiophen-3-ylmethyl, tetrahydro-pyran-4-yl,5-chloro-pyridin-2-yl, 1-carbamoyl-cyclobutyl, 5-fluoro-2-methyl-benzyl,2-morpholin-4-yl-2-pyridin-3-yl-ethyl, 1-(3-methoxy-phenyl)-cyclobutyl,5-methyl-pyridin-2-yl, 1-(tetrahydro-furan-2-yl)methyl,1-dimethylaminomethyl-cyclopentyl, 2-(4-fluoro-phenyl)-1-methyl-ethyl,benzothiazol-2-yl, 1-(2-fluoro-phenyl)-cyclopropyl,1-(2-methoxy-ethyl)-piperidin-4-yl, 2-hydroxy-1-pyridin-4-yl-ethyl,1-(3,3,3-trifluoro-propyl)-azetidin-3-ylmethyl,6-pyrrolidin-1-yl-pyridin-2-ylmethyl,1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl, 2,3-dimethoxy-benzyl,3-cyano-5-methyl-pyridin-2-yl, 2,3-dihydro-benzofuran-3-yl,1-hydroxymethyl-cyclohexyl, 2,5-difluoro-benzyl, 4-dimethylamino-benzyl,4-hydroxy-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl,4-trifluoromethyl-pyridin-2-yl, 5-methyl-thiazol-2-yl,6-trifluoromethyl-pyridin-3-yl, 5-hydroxy-1H-pyrazol-3-yl,2-thiomorpholin-4-yl-ethyl, benzo[1,3]dioxol-5-ylmethyl,2-amino-cyclohexyl,3-dimethylamino-1-oxo-tetrahydro-14-thiophen-3-ylmethyl,4-methyl-morpholin-2-ylmethyl, 1-(2-methoxy-phenyl)-cyclopropyl,2-carboxy-1-(4-fluorophenyl)propan-2-yl, pyridin-2-ylmethyl,pyridazin-3-yl, 4-pyridin-2-yl-thiazol-2-yl,1-(3,3,3-trifluoro-propyl)-piperidin-4-ylmethyl,6-chloro-2-methyl-pyridin-3-yl, 6-hydroxy-pyridin-3-yl,3-trifluoromethoxy-benzyl, 1-morpholin-4-yl-cyclopentylmethyl,1-pyridin-2-yl-cyclobutylmethyl,2-hydroxy-1-hydroxymethyl-1-methyl-ethyl, 5-hydroxymethyl-pyridin-2-yl,5-fluoro-1-oxy-pyridin-2-yl, 6-methoxy-pyridin-2-yl,1-methyl-1-pyridin-3-yl-ethyl, 6-methyl-pyridin-3-yl,2-hydroxy-1-hydroxymethyl-propyl, 2-chloro-pyridin-3-yl,3-methyl-3H-imidazol-4-ylmethyl, 6-fluoro-pyridin-2-yl,3-dimethylamino-benzyl, 6-morpholin-4-yl-pyridin-3-yl,1-o-tolyl-cyclopropyl, 1-(3,3,3-trifluoro-propyl)-piperidin-3-yl,6-methanesulfonyl-4-methyl-pyridin-3-yl, 2-methyl-quinolin-4-yl,1-(3,3,3-trifluoro-propyl)-pyrrolidin-3-ylmethyl, benzooxazol-2-yl,1-methyl-piperidin-4-ylmethyl,2-(2,6-dimethyl-morpholin-4-yl)-2-methyl-propyl,1-methyl-piperidin-2-ylmethyl, pyridin-4-ylmethyl,4-hydroxymethyl-pyridin-2-yl,5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl,6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl,1-(5-methyl-pyridin-2-yl)-ethyl, 2-fluoro-pyridin-3-yl, morpholin-4-yl,2-hydroxy-2-pyridin-4-yl-ethyl, pyridin-4-yl, 4-hydroxy-pyridin-2-yl,3-methoxy-benzyl, 1-oxy-pyridin-2-yl, 1-ethyl-propyl,6-carboxypyridin-2-yl, 1,2,2,6,6-pentamethyl-piperidin-4-yl,6-methoxy-pyridin-3-yl, cyclopentyl, morpholin-2-ylmethyl,1-(tert-butoxycarbonyl)azetidin-3-yl)methyl,2-dimethylamino-2-pyridin-3-yl-ethyl, 1-(4-methoxy-phenyl)-cyclobutyl,3-hydroxy-benzyl, tetrahydro-furan-2-ylmethyl,4-(tert-butoxycarbonyl)morpholin-2-ylmethyl,1-(3-fluoro-phenyl)-cyclopropyl, 2-o-tolyl-ethyl,3-hydroxymethyl-1-isobutyl-pyrrolidin-3-yl,1-(2-methoxy-ethyl)-azetidin-3-yl, 6-morpholin-4-yl-pyridin-2-ylmethyl,1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-ylmethyl,2-(4-fluoro-phenoxy)-ethyl, 2,6-dimethyl-pyrimidin-4-yl,1-hydroxymethyl-2-(3H-imidazol-4-yl)-ethyl, 4-methanesulfonyl-benzyl,1-pyridin-3-yl-cyclopropyl, 9-methyl-9-aza-bicyclo[3.3.1]non-1-yl,2,6-dimethyl-pyridin-3-yl, 4-hydroxy-benzyl, 2-oxo-2-phenyl-ethyl),1-methyl-1H-pyrazol-3-ylmethyl, pyrimidin-2-yl, 5-methyl-pyrazin-2-yl,1-(2-methoxy-pyridin-3-yl)-1-methyl-ethyl,6-methanesulfonyl-2-methyl-pyridin-3-yl, 2-hydroxy-benzyl,6-bromo-2-methyl-pyridin-3-yl, 2-methoxy-pyridin-3-yl,1-(4-chloro-phenyl)-cyclobutyl, 2-(pyridine-2-sulfonyl)-ethyl,1-pyridin-2-yl-cyclopropylmethyl,1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl, benzyl,3,5-dimethyl-pyrazin-2-yl, 1-(2-hydroxy-pyridin-3-yl)-1-methyl-ethyl,1-(ethoxycarbonyl)cyclobutyl,1-(tert-butoxycarbonyl)pyrrolidin-3-ylmethyl, quinolin-4-ylmethyl,2-(4-fluoro-phenyl)-1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethyl,2-morpholin-4-yl-pyridin-3-yl, 6-methyl-pyridin-2-yl,3-difluoromethoxy-benzyl, 4-hydroxy-1-methyl-piperidin-4-ylmethyl,1-(2,5-dimethylpyrrolidine-1-carbonyl)cyclopentyl, 2-methoxy-benzyl,6-methyl-pyridin-2-ylmethyl, 3-chloro-pyridin-4-yl,2-carboxypropan-2-yl, 6-chloro-pyridin-3-yl,2-hydroxy-2-pyridin-3-yl-ethyl, 1-p-tolyl-cyclopropyl,1-(3,3,3-trifluoro-propyl)-piperidin-4-yl, 4-methoxy-pyridin-2-yl,3-azepan-1-yl-2,2-dimethyl-propyl, 1-(tert-butoxycarbonyl)azetidin-3-yl,5-methyl-pyrazin-2-ylmethyl, 1-oxo-hexahydro-1λ⁴-thiopyran-4-yl,2-(2-chloro-phenyl)-ethyl,3-chloro-5-trifluoromethyl-pyridin-2-ylmethyl,2-hydroxy-1-hydroxymethyl-ethyl,(1-methyl-pyrrolidin-2-yl)-pyridin-2-yl, 5-fluoro-2-hydroxy-phenyl,methyl, 4-(methoxycarbonyl)-1-methylpiperidin-4-yl,4-hydroxymethyl-1-methyl-piperidin-4-yl,2-(2-hydroxymethyl-pyrrolidin-1-yl)-ethyl, 1-phenyl-cyclohexyl,3-methyl-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl, 1-cyano-cyclohexyl,1-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl, 2-cyanopropan-2-yl,3-methyl-1-phenylureido, 1-carbamoyl-2,2-dimethyl-propyl,tert-butylamino, 2,2,2-trifluoro-1,1-dimethyl-ethyl,2,2-dimethyl-1-methylcarbamoyl-propyl, 1-cyclopropyl-ethyl, amino,N-tert-butylmethylsulfonamido, 1,1-dimethyl-prop-2-ynyl,2-methyl-1-(phosphonooxy)propan-2-yl, 1-tert-butyl-3-methylureido,4-cyano-tetrahydro-pyran-4-yl, 1-methyl-cyclobutyl,1-hydroxymethyl-2-methyl-propyl, cyclobutylamino, 1-cyano-cyclopentyl,cyano-dimethyl-methyl, 2,2-dimethyl-1-(methylcarbamoyl)-propyl,phenylamino, 1-hydroxymethyl-propyl,1-methyl-1-(1H-tetrazol-5-yl)-ethyl,3,3-dimethyl-1-(phosphonooxy)butan-2-yl),2-hydroxy-1-tetrahydro-pyran-4-yl-ethyl, 1,2-dimethyl-propyl,1-pyridin-2-yl-cyclobutyl, 1-hydroxymethyl-2-phenyl-ethyl,4-methylcarbamoyl-tetrahydro-pyran-4-yl,1-methyl-1-methylcarbamoyl-ethyl,2,2-dimethyl-1-morpholin-4-ylmethyl-propyl,1-methylcarbamoyl-cyclopent-3-enyl,2-methoxy-2-oxo-1-(pyridin-2-yl)ethyl,methylcarbamoyl-pyridin-2-yl-methyl, 1-methylcarbamoyl-cyclopentyl,1-(tert-butylcarbamoyl)-2,2-dimethyl-propyl,2,2-dimethyl-1-(pyridin-2-ylcarbamoyl)-propyl,1-(pyridin-2-ylcarbamoyl)-cyclobutyl, 1-methylcarbamoyl-cyclobutyl,2-(methylamino)-2-oxo-1-phenylethyl, pyrrolidin-1-yl, piperidin-1-yl,2,6-dimethyl-piperidin-1-yl, 1-cyclopropylcarbamoyl-2,2-dimethyl-propyl,2,2-dimethyl-1-(2,2,2-trifluoro-ethylcarbamoyl)-propyl,1-ethylcarbamoyl-2,2-dimethyl-propyl,2-hydroxy-1-(tetrahydro-pyran-4-yl)-ethyl,N-cyclobutylmethylsulfonamido, N-phenylmethylsulfonamido,1-cyclopropyl-2-hydroxy-ethyl, 1,2,2-trimethyl-propyl,2-oxo-1-(pyridin-2-yl)-2-(2,2,2-trifluoroethylamino)ethyl,2,2-dimethyl-1-pyridin-2-yl-propyl,1-methoxy-3,3-dimethyl-1-oxobutan-2-yl, 1-carboxy-2,2-dimethylpropyl,1-(hydroxy-methyl-carbamoyl)-2,2-dimethyl-propyl,1-dimethylcarbamoyl-2,2-dimethyl-propyl,1-(azetidine-1-carbonyl)-2,2-dimethyl-propyl,1-methoxycarbamoyl-2,2-dimethyl-propyl,1-(methoxy-methyl-carbamoyl)-2,2-dimethyl-propyl,1-tert-butoxycarbamoyl-2,2-dimethyl-propyl, and2,2-dimethyl-1-pyridin-2-yl-propyl.

In some embodiments, R⁸ is H. In some embodiments, R⁸ is2-methyl-2-morpholin-4-yl-propyl. In some embodiments, R⁸ is1-hydroxymethyl-2,2-dimethyl-propyl. In some embodiments, R⁸ is2-(tert-butoxycarbonylamino)cyclohexyl. In some embodiments, R⁸ is1-phenyl-cyclopropyl. In some embodiments, R⁸ is5-trifluoromethyl-pyridin-2-yl. In some embodiments, R⁸ is1-methyl-1-phenyl-ethyl. In some embodiments, R⁸ is1-(2-methoxy-ethyl)-pyrrolidin-3-ylmethyl. In some embodiments, R⁸ is1-(methoxycarbonyl)cyclopropyl. In some embodiments, R⁸ istetrahydro-pyran-4-ylmethyl. In some embodiments, R⁸ is1-(tert-butoxycarbonyl)piperidin-4-yl. In some embodiments, R⁸ is1-(4-fluoro-phenyl)-cyclopropyl. In some embodiments, R⁸ is6-methyl-pyridin-3-ylmethyl. In some embodiments, R⁸ is2-hydroxy-1-phenyl-ethyl. In some embodiments, R⁸ is1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl. In some embodiments, R⁸ is2-hydroxy-1,1-dimethyl-ethyl. In some embodiments, R⁸ is2-(5-hydroxy-1H-indol-3-yl)-ethyl. In some embodiments, R⁸ is1-hydroxymethyl-cyclopropyl. In some embodiments, R⁸ is3-chloro-5-methyl-pyridin-2-yl. In some embodiments, R⁸ is6-fluoro-pyridin-3-yl. In some embodiments, R⁸ is1-(3-fluoro-phenyl)-cyclobutyl. In some embodiments, R⁸ is2-methyl-pyridin-3-yl. In some embodiments, R⁸ is2-hydroxy-1-(tetrahydro-furan-3-yl)-ethyl. In some embodiments, R⁸ is2-(pyridin-3-yloxy)-propyl. In some embodiments, R⁸ iscarbamoyl-phenyl-methyl. In some embodiments, R⁸ is5-fluoro-2-methoxy-phenyl. In some embodiments, R⁸ is 2-methoxy-ethyl.In some embodiments, R⁸ is 2,3-dihydroxy-propyl. In some embodiments, R⁸is 1-(tert-butoxycarbonyl)pyrrolidin-3-yl. In some embodiments, R⁸ is2-oxo-2-phenyl-ethyl. In some embodiments, R⁸ is1-(3,3,3-trifluoro-propyl)-azetidin-3-yl. In some embodiments, R⁸ is2-hydroxy-1-pyridin-2-yl-ethyl. In some embodiments, R⁸ is3-hydroxy-pyridin-4-yl. In some embodiments, R⁸ is1-methyl-1-pyridin-4-yl-ethyl. In some embodiments, R⁸ is1-hydroxymethyl-2-3H-imidazol-4-yl-ethyl. In some embodiments, R⁸ is4-hydroxy-3-methoxy-benzyl. In some embodiments, R⁸ is5-fluoro-2-oxo-2,3-dihydro-pyrimidin-4-yl. In some embodiments, R⁸ is1-(4-fluoro-phenyl)-3-hydroxy-propyl. In some embodiments, R⁸ is1-pyridin-4-yl-cyclopropyl. In some embodiments, In some embodiments, R⁸is 2-hydroxy-1-pyridin-3-yl-ethyl. In some embodiments, R⁸ is1,1-dimethyl-2-(4-methyl-piperidin-1-yl)-ethyl. In some embodiments, R⁸is 6-cyano-pyridin-3-yl. In some embodiments, R⁸ is5-fluoro-pyridin-2-yl. In some embodiments, R⁸ is 2,5-dimethyl-benzyl.In some embodiments, R⁸ is 1-isopropyl-piperidin-4-yl. In someembodiments, R⁸ is 2-methoxy-1-methoxymethyl-ethyl. In some embodiments,R⁸ is 2,3-dimethyl-benzyl. In some embodiments, R⁸ is1-pyridin-2-yl-ethyl. In some embodiments, R⁸ is6-chloro-pyridin-3-ylmethyl. In some embodiments, R⁸ is3-methyl-pyridin-2-yl. In some embodiments, R⁸ is 2-hydroxy-indan-1-yl.In some embodiments, R⁸ is (1S,2S)-2-hydroxy-indan-1-yl. In someembodiments, R⁸ is (1S,2R)-2-hydroxy-indan-1-yl. In some embodiments, R⁸is (1R,2R)-2-hydroxy-indan-1-yl. In some embodiments, R⁸ is(1R,2S)-2-hydroxy-indan-1-yl. In some embodiments, R⁸ is1-hydroxymethyl-cyclobutyl. In some embodiments, R⁸ is2-(4-chloro-phenyl)-1,1-dimethyl-ethyl. In some embodiments, R⁸ is3-hydroxy-pyridin-2-ylmethyl. In some embodiments, R⁸ is3-methyl-pyridin-4-yl. In some embodiments, R⁸ is5-tert-butyl-isoxazol-3-yl. In some embodiments, R⁸ is1-(6-methoxy-pyridin-3-yl)-1-methyl-ethyl. In some embodiments, R⁸ is1H-benzoimidazol-2-yl. In some embodiments, R⁸ is tert-butyl. In someembodiments, R⁸ is 4-phenyl-thiazol-2-yl. In some embodiments, R⁸ is1-(2-fluoro-phenyl)-cyclobutyl. In some embodiments, R⁸ is2,4-dimethoxy-benzyl. In some embodiments, R⁸ is5-bromo-3-methyl-pyridin-2-yl. In some embodiments, R⁸ is4-benzyl-morpholin-2-ylmethyl. In some embodiments, R⁸ is6-trifluoromethyl-pyridin-3-ylmethyl. In some embodiments, R⁸ istetrahydro-furan-3-yl. In some embodiments, R⁸ is pyridin-3-ylmethyl. Insome embodiments, R⁸ is pyrazin-2-yl. In some embodiments, R⁸ ispiperidin-4-yl. In some embodiments, R⁸ is1-(6-hydroxy-pyridin-3-yl)-1-methyl-ethyl. In some embodiments, R⁸ is1-methyl-1-pyridin-2-yl-ethyl. In some embodiments, R⁸ is1-hydroxymethyl-cyclopentyl. In some embodiments, R⁸ is1-aza-bicyclo[2.2.2]oct-3-yl. In some embodiments, R⁸ is2-hydroxy-cyclopentyl. In some embodiments, R⁸ is2-hydroxy-1-(hydroxymethyl)-propyl. In some embodiments, R⁸ is1-(tert-butoxycarbonyl)piperidin-4-yl)methyl. In some embodiments, R⁸ is3,5-dimethoxy-phenyl. In some embodiments, R⁸ is6-fluoro-4H-benzo[1,3]dioxin-8-ylmethyl. In some embodiments, R⁸ is4,6-dimethyl-pyridin-2-yl. In some embodiments, R⁸ is1,1-dimethyl-2-morpholin-4-yl-ethyl. In some embodiments, R⁸ is2-hydroxy-cyclohexylmethyl. In some embodiments, R⁸ is1-(4-methoxy-phenyl)-cyclopropyl. In some embodiments, R⁸ is1-ethyl-pyrrolidin-2-ylmethyl. In some embodiments, R⁸ is indan-1-yl. Insome embodiments, R⁸ is pyrimidin-4-yl. In some embodiments, R⁸ is2-fluoro-4-methanesulfonyl-phenyl. In some embodiments, R⁸ is6-hydroxy-pyridin-2-yl. In some embodiments, R⁸ is cyclobutyl. In someembodiments, R⁸ is 1-(3-methoxy-phenyl)-cyclopropyl. In someembodiments, R⁸ is 1-(3,3,3-trifluoro-propyl)-pyrrolidin-3-yl. In someembodiments, R⁸ is 2-hydroxy-pyridin-3-yl. In some embodiments, R⁸ is4-difluoromethoxy-benzyl. In some embodiments, R⁸ is1-piperidin-1-yl-cyclopentylmethyl. In some embodiments, R⁸ is3-hydroxy-3-methyl-butyl. In some embodiments, R⁸ is1-(4-fluoro-phenyl)-cyclobutyl. In some embodiments, R⁸ is4-methoxy-benzyl. In some embodiments, R⁸ is pyridin-2-yl. In someembodiments, R⁸ is 2-hydroxy-2-phenyl-ethyl. In some embodiments, R⁸ is2-hydroxymethyl-2,3-dihydro-indol-1-yl. In some embodiments, R⁸ is3-hydroxy-pyridin-2-yl. In some embodiments, R⁸ is4-dimethylamino-tetrahydro-pyran-4-ylmethyl. In some embodiments, R⁸ is2-(4-fluoro-phenyl)-ethyl. In some embodiments, R⁸ is1-(2-methoxy-ethyl)-piperidin-4-ylmethyl. In some embodiments, R⁸ is2-morpholin-4-yl-ethyl. In some embodiments, R⁸ is1-(tert-butoxycarbonyl)-4-carboxypiperidin-4-yl. In some embodiments, R⁸is quinolin-3-yl. In some embodiments, R⁸ is1-morpholin-4-ylmethyl-cyclopentyl. In some embodiments, R⁸ is1,4-dimethyl-1H-pyrrol-2-ylmethyl. In some embodiments, R⁸ is2-hydroxy-2-pyridin-2-yl-ethyl. In some embodiments, R⁸ is pyridin-3-yl.In some embodiments, R⁸ is 2-dimethylamino-benzyl. In some embodiments,R⁸ is tetrahydro-thiopyran-4-yl. In some embodiments, R⁸ is1-m-tolyl-cyclopropyl. In some embodiments, R⁸ is1-(2-methoxy-ethyl)-piperidin-3-yl. In some embodiments, R⁸ is5-methoxy-pyridin-2-ylmethyl. In some embodiments, R⁸ is2-hydroxy-1-pyridin-4-yl-ethyl. In some embodiments, R⁸ is4-methyl-pyridin-2-yl. In some embodiments, R⁸ is4-carboxy-2-fluorophenyl. In some embodiments, R⁸ is6-methanesulfonyl-pyridin-3-yl. In some embodiments, R⁸ is1-o-tolyl-cyclobutyl. In some embodiments, R⁸ is1,1-dimethyl-2-pyrrolidin-1-yl-ethyl. In some embodiments, R⁸ is2,6-dimethoxy-pyridin-3-yl. In some embodiments, R⁸ is pyridin-2-yl. Insome embodiments, R⁸ is 4-hydroxymethyl-tetrahydro-pyran-4-yl. In someembodiments, R⁸ is 2-(1H-imidazol-4-yl)-ethyl. In some embodiments, R⁸is 3-fluoro-pyridin-4-yl. In some embodiments, R⁸ is1-carbamoyl-2-phenyl-ethyl. In some embodiments, R⁸ isoxazol-4-ylmethyl. In some embodiments, R⁸ is 6-methoxy-pyrimidin-4-yl.In some embodiments, R⁸ is 1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl. Insome embodiments, R⁸ is 1-methoxy-1-oxo-3-phenylpropan-2-yl. In someembodiments, R⁸ is 1-(2-methoxy-ethyl)-pyrrolidin-3-yl. In someembodiments, R⁸ is 1-(6-methyl-pyridin-2-yl)-ethyl. In some embodiments,R⁸ is 2-hydroxy-1-(4-hydroxy-phenyl)-ethyl. In some embodiments, R⁸ is2-methoxy-pyridin-4-yl. In some embodiments, R⁸ is1-pyridin-2-yl-cyclopropyl. In some embodiments, R⁸ is1-(tert-butoxycarbonyl)piperidin-3-yl. In some embodiments, R⁸ is3-methyl-pyridin-2-ylmethyl. In some embodiments, R⁸ is3-fluoro-pyridin-2-yl. In some embodiments, R⁸ is1-pyridin-4-yl-cyclobutyl. In some embodiments, R⁸ is2-carboxy-1-(pyridin-3-yl)ethyl. In some embodiments, R⁸ is2-hydroxy-1-methyl-ethyl. In some embodiments, R⁸ is1-(methoxycarbonyl)cyclohexyl. In some embodiments, R⁸ is3-hydroxymethyl-pyridin-4-yl. In some embodiments, R⁸ is2-hydroxy-1-phenyl-ethyl. In some embodiments, R⁸ is3-dimethylamino-tetrahydro-thiophen-3-ylmethyl. In some embodiments, R⁸is tetrahydro-pyran-4-yl. In some embodiments, R⁸ is5-chloro-pyridin-2-yl. In some embodiments, R⁸ is1-carbamoyl-cyclobutyl. In some embodiments, R⁸ is5-fluoro-2-methyl-benzyl. In some embodiments, R⁸ is2-morpholin-4-yl-2-pyridin-3-yl-ethyl. In some embodiments, R⁸ is1-(3-methoxy-phenyl)-cyclobutyl. In some embodiments, R⁸ is5-methyl-pyridin-2-yl. In some embodiments, R⁸ is1-(tetrahydro-furan-2-yl)methyl. In some embodiments, R⁸ is1-dimethylaminomethyl-cyclopentyl. In some embodiments, R⁸ is2-(4-fluoro-phenyl)-1-methyl-ethyl. In some embodiments, R⁸ isbenzothiazol-2-yl. In some embodiments, R⁸ is1-(2-fluoro-phenyl)-cyclopropyl. In some embodiments, R⁸ is1-(2-methoxy-ethyl)-piperidin-4-yl. In some embodiments, R⁸ is2-hydroxy-1-pyridin-4-yl-ethyl. In some embodiments, R⁸ is1-(3,3,3-trifluoro-propyl)-azetidin-3-ylmethyl. In some embodiments, R⁸is 6-pyrrolidin-1-yl-pyridin-2-ylmethyl. In some embodiments, R⁸ is1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl. In some embodiments, R⁸ is2,3-dimethoxy-benzyl. In some embodiments, R⁸ is3-cyano-5-methyl-pyridin-2-yl. In some embodiments, R⁸ is2,3-dihydro-benzofuran-3-yl. In some embodiments, R⁸ is1-hydroxymethyl-cyclohexyl. In some embodiments, R⁸ is2,5-difluoro-benzyl. In some embodiments, R⁸ is 4-dimethylamino-benzyl.In some embodiments, R⁸ is4-hydroxy-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl. In some embodiments,R⁸ is 4-trifluoromethyl-pyridin-2-yl. In some embodiments, R⁸ is5-methyl-thiazol-2-yl. In some embodiments, R⁸ is6-trifluoromethyl-pyridin-3-yl. In some embodiments, R⁸ is5-hydroxy-1H-pyrazol-3-yl. In some embodiments, R⁸ is2-thiomorpholin-4-yl-ethyl. In some embodiments, R⁸ isbenzo[1,3]dioxol-5-ylmethyl. In some embodiments, R⁸ is2-amino-cyclohexyl. In some embodiments, R⁸ is3-dimethylamino-1-oxo-tetrahydro-1λ⁴-thiophen-3-ylmethyl. In someembodiments, R⁸ is 4-methyl-morpholin-2-ylmethyl. In some embodiments,R⁸ is 1-(2-methoxy-phenyl)-cyclopropyl. In some embodiments, R⁸ is2-carboxy-1-(4-fluorophenyl)propan-2-yl. In some embodiments, R⁸ ispyridin-2-ylmethyl. In some embodiments, R⁸ is pyridazin-3-yl. In someembodiments, R⁸ is 4-pyridin-2-yl-thiazol-2-yl. In some embodiments, R⁸is 1-(3,3,3-trifluoro-propyl)-piperidin-4-ylmethyl. In some embodiments,R⁸ is 6-chloro-2-methyl-pyridin-3-yl. In some embodiments, R⁸ is6-hydroxy-pyridin-3-yl. In some embodiments, R⁸ is3-trifluoromethoxy-benzyl. In some embodiments, R⁸ is1-morpholin-4-yl-cyclopentylmethyl. In some embodiments, R⁸ is1-pyridin-2-yl-cyclobutylmethyl. In some embodiments, R⁸ is2-hydroxy-1-hydroxymethyl-1-methyl-ethyl. In some embodiments, R⁸ is5-hydroxymethyl-pyridin-2-yl. In some embodiments, R⁸ is5-fluoro-1-oxy-pyridin-2-yl. In some embodiments, R⁸ is6-methoxy-pyridin-2-yl. In some embodiments, R⁸ is1-methyl-1-pyridin-3-yl-ethyl. In some embodiments, R⁸ is6-methyl-pyridin-3-yl. In some embodiments, R⁸ is2-hydroxy-1-hydroxymethyl-propyl. In some embodiments, R⁸ is2-chloro-pyridin-3-yl. In some embodiments, R⁸ is3-methyl-3H-imidazol-4-ylmethyl. In some embodiments, R⁸ is6-fluoro-pyridin-2-yl. In some embodiments, R⁸ is3-dimethylamino-benzyl. In some embodiments, R⁸ is6-morpholin-4-yl-pyridin-3-yl. In some embodiments, R⁸ is1-o-tolyl-cyclopropyl. In some embodiments, R⁸ is1-(3,3,3-trifluoro-propyl)-piperidin-3-yl. In some embodiments, R⁸ is6-methanesulfonyl-4-methyl-pyridin-3-yl. In some embodiments, R⁸ is2-methyl-quinolin-4-yl. In some embodiments, R⁸ is1-(3,3,3-trifluoro-propyl)-pyrrolidin-3-ylmethyl. In some embodiments,R⁸ is benzooxazol-2-yl. In some embodiments, R⁸ is1-methyl-piperidin-4-ylmethyl. In some embodiments, R⁸ is2-(2,6-dimethyl-morpholin-4-yl)-2-methyl-propyl. In some embodiments, R⁸is 1-methyl-piperidin-2-ylmethyl. In some embodiments, R⁸ ispyridin-4-ylmethyl. In some embodiments, R⁸ is4-hydroxymethyl-pyridin-2-yl. In some embodiments, R⁸ is5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl. In some embodiments, R⁸ is6,6-dimethyl-bicyclo[3.1.1]hept-2-ylmethyl. In some embodiments, R⁸ is1-(5-methyl-pyridin-2-yl)-ethyl. In some embodiments, R⁸ is2-fluoro-pyridin-3-yl. In some embodiments, R⁸ is morpholin-4-yl. Insome embodiments, R⁸ is 2-hydroxy-2-pyridin-4-yl-ethyl. In someembodiments, R⁸ is pyridin-4-yl. In some embodiments, R⁸ is4-hydroxy-pyridin-2-yl. In some embodiments, R⁸ is 3-methoxy-benzyl. Insome embodiments, R⁸ is 1-oxy-pyridin-2-yl. In some embodiments, R⁸ is1-ethyl-propyl. In some embodiments, R⁸ is 6-carboxypyridin-2-yl. Insome embodiments, R⁸ is 1,2,2,6,6-pentamethyl-piperidin-4-yl. In someembodiments, R⁸ is 6-methoxy-pyridin-3-yl. In some embodiments, R⁸ iscyclopentyl. In some embodiments, R⁸ is morpholin-2-ylmethyl. In someembodiments, R⁸ is 1-(tert-butoxycarbonyl)azetidin-3-yl)methyl. In someembodiments, R⁸ is 2-dimethylamino-2-pyridin-3-yl-ethyl. In someembodiments, R⁸ is 1-(4-methoxy-phenyl)-cyclobutyl. In some embodiments,R⁸ is 3-hydroxy-benzyl. In some embodiments, R⁸ istetrahydro-furan-2-ylmethyl. In some embodiments, R⁸ is4-(tert-butoxycarbonyl)morpholin-2-ylmethyl. In some embodiments, R⁸ is1-(3-fluoro-phenyl)-cyclopropyl. In some embodiments, R⁸ is2-o-tolyl-ethyl. In some embodiments, R⁸ is3-hydroxymethyl-1-isobutyl-pyrrolidin-3-yl. In some embodiments, R⁸ is1-(2-methoxy-ethyl)-azetidin-3-yl. In some embodiments, R⁸ is6-morpholin-4-yl-pyridin-2-ylmethyl. In some embodiments, R⁸ is1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-ylmethyl. In some embodiments, R⁸ is2-(4-fluoro-phenoxy)-ethyl. In some embodiments, R⁸ is2,6-dimethyl-pyrimidin-4-yl. In some embodiments, R⁸ is1-hydroxymethyl-2-(3H-imidazol-4-yl)-ethyl. In some embodiments, R⁸ is4-methanesulfonyl-benzyl. In some embodiments, R⁸ is1-pyridin-3-yl-cyclopropyl. In some embodiments, R⁸ is9-methyl-9-aza-bicyclo[3.3.1]non-1-yl. In some embodiments, R⁸ is2,6-dimethyl-pyridin-3-yl. In some embodiments, R⁸ is 4-hydroxy-benzyl.In some embodiments, R⁸ is 2-oxo-2-phenyl-ethyl). In some embodiments,R⁸ is 1-methyl-1H-pyrazol-3-ylmethyl. In some embodiments, R⁸ ispyrimidin-2-yl. In some embodiments, R⁸ is 5-methyl-pyrazin-2-yl. Insome embodiments, R⁸ is 1-(2-methoxy-pyridin-3-yl)-1-methyl-ethyl. Insome embodiments, R⁸ is 6-methanesulfonyl-2-methyl-pyridin-3-yl. In someembodiments, R⁸ is 2-hydroxy-benzyl. In some embodiments, R⁸ is6-bromo-2-methyl-pyridin-3-yl. In some embodiments, R⁸ is2-methoxy-pyridin-3-yl. In some embodiments, R⁸ is1-(4-chloro-phenyl)-cyclobutyl. In some embodiments, R⁸ is2-(pyridine-2-sulfonyl)-ethyl. In some embodiments, R⁸ is1-pyridin-2-yl-cyclopropylmethyl. In some embodiments, R⁸ is1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl. In some embodiments, R⁸ isbenzyl. In some embodiments, R⁸ is 3,5-dimethyl-pyrazin-2-yl. In someembodiments, R⁸ is 1-(2-hydroxy-pyridin-3-yl)-1-methyl-ethyl. In someembodiments, R⁸ is 1-(ethoxycarbonyl)cyclobutyl. In some embodiments, R⁸is 1-(tert-butoxycarbonyl)pyrrolidin-3-ylmethyl. In some embodiments, R⁸is quinolin-4-ylmethyl. In some embodiments, R⁸ is2-(4-fluoro-phenyl)-1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethyl. In someembodiments, R⁸ is 2-morpholin-4-yl-pyridin-3-yl. In some embodiments,R⁸ is 6-methyl-pyridin-2-yl. In some embodiments, R⁸ is3-difluoromethoxy-benzyl. In some embodiments, R⁸ is4-hydroxy-1-methyl-piperidin-4-ylmethyl. In some embodiments, R⁸ is1-(2,5-dimethylpyrrolidine-1-carbonyl)cyclopentyl. In some embodiments,R⁸ is 2-methoxy-benzyl. In some embodiments, R⁸ is6-methyl-pyridin-2-ylmethyl. In some embodiments, R⁸ is3-chloro-pyridin-4-yl. In some embodiments, R⁸ is 2-carboxypropan-2-yl.In some embodiments, R⁸ is 6-chloro-pyridin-3-yl. In some embodiments,R⁸ is 2-hydroxy-2-pyridin-3-yl-ethyl. In some embodiments, R⁸ is1-p-tolyl-cyclopropyl. In some embodiments, R⁸ is1-(3,3,3-trifluoro-propyl)-piperidin-4-yl. In some embodiments, R⁸ is4-methoxy-pyridin-2-yl. In some embodiments, R⁸ is3-azepan-1-yl-2,2-dimethyl-propyl. In some embodiments, R⁸ is1-(tert-butoxycarbonyl)azetidin-3-yl. In some embodiments, R⁸ is5-methyl-pyrazin-2-ylmethyl. In some embodiments, R⁸ is1-oxo-hexahydro-1λ⁴-thiopyran-4-yl. In some embodiments, R⁸ is2-(2-chloro-phenyl)-ethyl. In some embodiments, R⁸ is3-chloro-5-trifluoromethyl-pyridin-2-ylmethyl. In some embodiments, R⁸is 2-hydroxy-1-hydroxymethyl-ethyl. In some embodiments, R⁸ is(1-methyl-pyrrolidin-2-yl)-pyridin-2-yl. In some embodiments, R⁸ is5-fluoro-2-hydroxy-phenyl. In some embodiments, R⁸ is methyl. In someembodiments, R⁸ is 4-(methoxycarbonyl)-1-methylpiperidin-4-yl. In someembodiments, R⁸ is 4-hydroxymethyl-1-methyl-piperidin-4-yl. In someembodiments, R⁸ is 2-(2-hydroxymethyl-pyrrolidin-1-yl)-ethyl. In someembodiments, R⁸ is 1-phenyl-cyclohexyl. In some embodiments, R⁸ is3-methyl-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl. In some embodiments, R⁸is 1-cyano-cyclohexyl. In some embodiments, R⁸ is1-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl. In some embodiments, R⁸is 2-cyanopropan-2-yl. In some embodiments, R⁸ is3-methyl-1-phenylureido. In some embodiments, R⁸ is1-carbamoyl-2,2-dimethyl-propyl. In some embodiments, R⁸ istert-butylamino. In some embodiments, R⁸ is2,2,2-trifluoro-1,1-dimethyl-ethyl. In some embodiments, R⁸ is2,2-dimethyl-1-methylcarbamoyl-propyl. In some embodiments, R⁸ is1-cyclopropyl-ethyl. In some embodiments, R⁸ is amino. In someembodiments, R⁸ is N-tert-butylmethylsulfonamido. In some embodiments,R⁸ is 1,1-dimethyl-prop-2-ynyl. In some embodiments, R⁸ is2-methyl-1-(phosphonooxy)propan-2-yl. In some embodiments, R⁸ is1-tert-butyl-3-methylureido. In some embodiments, R⁸ is4-cyano-tetrahydro-pyran-4-yl. In some embodiments, R⁸ is1-methyl-cyclobutyl. In some embodiments, R⁸ is1-hydroxymethyl-2-methyl-propyl. In some embodiments, R⁸ iscyclobutylamino. In some embodiments, R⁸ is 1-cyano-cyclopentyl. In someembodiments, R⁸ is cyano-dimethyl-methyl. In some embodiments, R⁸ is2,2-dimethyl-1-(methylcarbamoyl)-propyl. In some embodiments, R⁸ isphenylamino. In some embodiments, R⁸ is 1-hydroxymethyl-propyl. In someembodiments, R⁸ is 1-methyl-1-(1H-tetrazol-5-yl)-ethyl. In someembodiments, R⁸ is 3,3-dimethyl-1-(phosphonooxy)butan-2-yl). In someembodiments, R⁸ is 2-hydroxy-1-tetrahydro-pyran-4-yl-ethyl. In someembodiments, R⁸ is 1,2-dimethyl-propyl. In some embodiments, R⁸ is1-pyridin-2-yl-cyclobutyl. In some embodiments, R⁸ is1-hydroxymethyl-2-phenyl-ethyl. In some embodiments, R⁸ is4-methylcarbamoyl-tetrahydro-pyran-4-yl. In some embodiments, R⁸ is1-methyl-1-methylcarbamoyl-ethyl. In some embodiments, R⁸ is2,2-dimethyl-1-morpholin-4-ylmethyl-propyl. In some embodiments, R⁸ is1-methylcarbamoyl-cyclopent-3-enyl. In some embodiments, R⁸ is2-methoxy-2-oxo-1-(pyridin-2-yl)ethyl. In some embodiments, R⁸ ismethylcarbamoyl-pyridin-2-yl-methyl. In some embodiments, R⁸ is1-methylcarbamoyl-cyclopentyl. In some embodiments, R⁸ is1-(tert-butylcarbamoyl)-2,2-dimethyl-propyl. In some embodiments, R⁸ is2,2-dimethyl-1-(pyridin-2-ylcarbamoyl)-propyl. In some embodiments, R⁸is 1-(pyridin-2-ylcarbamoyl)-cyclobutyl. In some embodiments, R⁸ is1-methylcarbamoyl-cyclobutyl. In some embodiments, R⁸ is2-(methylamino)-2-oxo-1-phenylethyl. In some embodiments, R⁸ ispyrrolidin-1-yl. In some embodiments, R⁸ is piperidin-1-yl. In someembodiments, R⁸ is 2,6-dimethyl-piperidin-1-yl. In some embodiments, R⁸is 1-cyclopropylcarbamoyl-2,2-dimethyl-propyl. In some embodiments, R⁸is 2,2-dimethyl-1-(2,2,2-trifluoro-ethylcarbamoyl)-propyl. In someembodiments, R⁸ is 1-ethylcarbamoyl-2,2-dimethyl-propyl. In someembodiments, R⁸ is 2-hydroxy-1-(tetrahydro-pyran-4-yl)-ethyl. In someembodiments, R⁸ is N-cyclobutylmethylsulfonamido. In some embodiments,R⁸ is N-phenylmethylsulfonamido. In some embodiments, R⁸ is1-cyclopropyl-2-hydroxy-ethyl. In some embodiments, R⁸ is1,2,2-trimethyl-propyl. In some embodiments, R⁸ is2-oxo-1-(pyridin-2-yl)-2-(2,2,2-trifluoroethylamino)ethyl. In someembodiments, R⁸ is 2,2-dimethyl-1-pyridin-2-yl-propyl. In someembodiments, R⁸ is 1-methoxy-3,3-dimethyl-1-oxobutan-2-yl. In someembodiments, R⁸ is 1-carboxy-2,2-dimethylpropyl. In some embodiments, R⁸is 1-(hydroxy-methyl-carbamoyl)-2,2-dimethyl-propyl. In someembodiments, R⁸ is 1-dimethylcarbamoyl-2,2-dimethyl-propyl. In someembodiments, R⁸ is 1-(azetidine-1-carbonyl)-2,2-dimethyl-propyl. In someembodiments, R⁸ is 1-methoxycarbamoyl-2,2-dimethyl-propyl. In someembodiments, R⁸ is 1-(methoxy-methyl-carbamoyl)-2,2-dimethyl-propyl. Insome embodiments, R⁸ is 1-tert-butoxycarbamoyl-2,2-dimethyl-propyl. Insome embodiments, R⁸ is 2,2-dimethyl-1-pyridin-2-yl-propyl. In someembodiments, R⁸ is fluoromethyl. In some embodiments, R⁸ is2,2,2-trifluoroethylamino. In some embodiments, R⁸ is(1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl)amino. In some embodiments, R⁸is 1-hydroxycarbamoyl-2,2-dimethyl-propyl. In some embodiments, R⁸ is1-hydroxymethyl-2-methyl-butyl. In some embodiments, R⁸ is1-(2-hydroxy-ethylcarbamoyl)-2,2-dimethyl-propyl. In some embodiments,R⁸ is 1,1-bis-hydroxymethyl-propyl. In some embodiments, R⁸ is1-(5-fluoro-pyridin-2-yl)-2,2-dimethyl-propyl. In some embodiments, R⁸is 4-hydroxymethyl-tetrahydro-2H-pyran-4-yl. In some embodiments, R⁸ is1-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)-2-methylpropan-2-yl.In some embodiments, R⁸ is1-(2-amino-3-methylbutanoyloxy)-3-methylbutan-2-yl. In some embodiments,R⁸ is 1-(2-amino-3-methylbutanoyloxy)-2-methylpropan-2-yl. In someembodiments, R⁸ is 2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-ethyl. In someembodiments, R⁸ is 1-(4-carboxybutanoyloxy)-2-methylpropan-2-yl. In someembodiments, R⁸ is 1-(4-carboxybutanoyloxy)-3-methylbutan-2-yl. In someembodiments, R⁸ is 1-(4-carboxybutanoyloxy)-3,3-dimethylbutan-2-yl. Insome embodiments, R⁸ is1-(2-amino-3-methylbutanoyloxy)-3,3-dimethylbutan-2-yl. In someembodiments, R⁸ is2-(2-amino-3-methylbutanoyloxy)-1-(tetrahydro-2H-pyran-4-yl)ethyl. Insome embodiments, R⁸ is 3,3,3-trifluoro-1-hydroxymethyl-propyl. In someembodiments, R⁸ is 3-fluoro-1-methoxy-3-methyl-1-oxobutan-2-yl. In someembodiments, R⁸ is1-ethoxy-4,4,4-trifluoro-1-oxo-3-(trifluoromethyl)butan-2-yl. In someembodiments, R⁸ is 2-fluoro-1-hydroxymethyl-2-methyl-propyl. In someembodiments, R⁸ is1-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)-3,3-dimethylbutan-2-yl.In some embodiments, R⁸ is 4,4,4-trifluoro-1-methoxy-1-oxobutan-2-yl. Insome embodiments, R⁸ is 2-fluoro-1,1-dimethyl-ethyl. In someembodiments, R⁸ is 3-fluoro-2-(fluoromethyl)-1-methoxy-1-oxopropan-2-yl.In some embodiments, R⁸ is2-fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl. In some embodiments, R⁸is 3-hydroxy-1-methoxy-2-methyl-1-oxopropan-2-yl. In some embodiments,R⁸ is 2-carboxy-1-hydroxypropan-2-yl. In some embodiments, R⁸ is2,2,2-trifluoroethylamino. In some embodiments, R⁸ is1-fluoromethyl-2-methyl-propyl. In some embodiments, R⁸ is1-fluoromethyl-2,2-dimethyl-propyl. In some embodiments, R⁸ is3-methyl-oxetan-3-yl. In some embodiments, R⁸ is1-fluoromethyl-cyclobutyl. In some embodiments, R⁸ is1,1-bis-hydroxymethyl-2-methyl-propyl. In some embodiments, R⁸ is1-trifluoromethyl-cyclopropyl. In some embodiments, R⁸ is1-methyl-cyclopropyl. In some embodiments, R⁸ is1-trifluoromethyl-cyclobutyl.

The Group R⁹:

In some embodiments, R⁹ is selected from H, C₁-C₆ alkyl, and C₃-C₇cycloalkyl.

In some embodiments, R⁹ is C₁-C₆ alkyl.

In some embodiments, R⁹ is C₃-C₇ cycloalkyl.

In some embodiments, R⁹ is selected from H, methyl, tert-butyl, andcyclobutyl.

In some embodiments, R⁹ is H.

In some embodiments, R⁹ is methyl.

In some embodiments, R⁹ is tert-butyl.

In some embodiments, R⁹ is cyclobutyl.

The Group R¹⁰:

In some embodiments, R¹⁰ is selected from: C₁-C₆ alkylene,heteroarylene, and heterocyclylene.

In some embodiments, R¹⁰ is selected from: 1,1-dimethylethylene,1,1-dimethylmethylene, ethylene, methylene, 1,4-piperidinylene,2,5-pyrazinylene, and 2,4-pyridinylene.

In some embodiments, R¹⁰ is C₁-C₆ alkylene.

In some embodiments, R¹⁰ is selected from: 1,1-dimethylethylene,1,1-dimethylmethylene, ethylene, and methylene.

In some embodiments, R¹⁰ is 1,1-dimethylethylene

In some embodiments, R¹⁰ is 1,1-dimethylmethylene.

In some embodiments, R¹⁰ is ethylene.

In some embodiments, R¹⁰ is methylene.

In some embodiments, R¹⁰ is heteroarylene.

In some embodiments, R¹⁰ is selected from: 2,5-pyrazinylene, and2,4-pyridinylene.

In some embodiments, R¹⁰ is heterocyclylene.

In some embodiments, R¹⁰ is 1,4-piperidinylene.

In some embodiments, R¹⁰ is absent.

The Group R¹¹:

In some embodiments, R¹¹ is selected from: —C(O)NH— and C₁-C₆ alkylene.

In some embodiments, R¹¹ is selected from: —C(O)NH— and methylene.

In some embodiments, R¹¹ is —C(O)NH—.

In some embodiments, R¹¹ is C₁-C₆ alkylene.

In some embodiments, R¹¹ is methylene.

In some embodiments, R¹¹ is absent.

The Group R¹²:

In some embodiments, R¹² is C₁-C₆ alkylene.

In some embodiments, R¹² is methylene.

In some embodiments, R¹² is 1,1-dimethyl-methylene.

In some embodiments, R¹² is absent.

The Group R¹³:

In some embodiments, R¹³ is selected from: C₁-C₆ alkyl, aryl, C₃-C₇cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆alkyl, aryl, and heteroaryl are each optionally substituted with one ortwo substituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylamino, C₁-C₆ alkylsulfonyl, amino, C₃-C₇ cycloalkyl, cyano, C₂-C₈dialkylamino, C₁-C₆ haloalkyl, halogen, and hydroxyl.

In some embodiments, R¹³ is selected from: C₁-C₆ alkyl, aryl, C₃-C₇cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆alkyl, aryl, and heteroaryl are each optionally substituted with one ortwo substituents selected from: fluoro, bromo, chloro, iodo, methoxy,cyano, methyl, tert-butyl, isopropyl, hydroxyl, ethyl,heptafluoropropyl, cyclobutyl, trifluoromethyl, cyclopropyl,dimethylamino, methoxy, ethoxy, methylamino, propyl, amino, andmethanesulfonyl.

In some embodiments, R¹³ is selected from: C₁-C₆ alkyl, aryl, C₃-C₇cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆alkyl, aryl, and heteroaryl are each optionally substituted with one ortwo substituents selected from: fluoro, bromo, chloro, methoxy, cyano,methyl, tert-butyl, isopropyl, hydroxyl, ethyl, heptafluoropropyl,cyclobutyl, trifluoromethyl, cyclopropyl, dimethylamino, methoxy,ethoxy, methylamino, propyl, amino, and methanesulfonyl.

In some embodiments, R¹³ is selected from: 2,4-difluoro-phenyl,2,4-dichloro-phenyl, 2-fluoro-4-methanesulfonyl-phenyl,2,6-difluoro-phenyl, 2,5-difluoro-phenyl, 4-methoxy-phenyl,4-cyano-phenyl, 4-fluoro-phenyl, phenyl, 2-fluoro-phenyl,3-fluoro-phenyl, o-tolyl, tert-butyl, isopropyl, 2,2-dimethylpropyl,hydroxyl, 2-hydroxy-2-methylpropyl, 1-oxo-hexahydro-1λ⁴-thiopyran-4-yl,1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl, tetrahydrothiopyran-4-yl,morpholin-4-yl, tetrahydro-pyran-4-yl,1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl, pyrazin-2-yl,5-ethyl-pyrazin-2-yl, 5-hydroxy-pyrazin-2-yl, 5-isopropyl-pyrazin-2-yl,5-heptafluoropropyl-pyrazin-2-yl, 5-cyclobutyl-pyrazin-2-yl,5-methyl-pyrazin-2-yl, 6-ethyl-pyrazin-2-yl,5-trifluoromethyl-pyrazin-2-yl, cyclopropyl, 5-cyclopropyl-pyrazin-2-yl,6-chloro-pyrazin-2-yl, 5-dimethylamino-pyrazin-2-yl, 4-cyano-phenyl,6-methoxy-pyridazin-3-yl, 6-chloro-pyridazin-3-yl, pyrimidin-5-yl,6-dimethylamino-pyrazin-2-yl, 6-methoxy-pyrazin-2-yl, 2-pyrimidin-4-yl,5-bromo-pyrazin-2-yl, 5-hydroxy-pyrazin-2-yl, 5-methoxy-pyrazin-2-yl,5-ethoxypyrazin-2-yl, 5-methylamino-pyrazin-2-yl, 5-bromo-pyridin-2-yl,pyridin-3-yl, 5-trifluoromethyl-pyridin-2-yl, 5-isopropyl-pyridin-2-yl,5-isopropyl-pyridin-2-yl, 5-methyl-pyridin-2-yl, 5-ethyl-pyridin-2-yl,5-methoxy-pyridin-2-yl, 4-trifluoromethyl-pyridin-2-yl,5-cyano-pyridin-2-yl, 5-dimethylamino-pyridin-2-yl,4-methyl-pyridin-2-yl, 5-chloro-4-methyl-pyridin-2-yl,5-chloro-4-trifluoromethyl-pyridin-2-yl, 4-trifluoromethyl-pyridin-2-yl,3-fluoro-pyridin-2-yl, 6-methyl-4-trifluoromethyl-pyridin-2-yl,3-methyl-pyridin-2-yl, 5-propyl-pyridin-2-yl,5-cyclopropyl-pyridin-2-yl, 5-fluoro-pyridin-2-yl,3,5-difluoro-pyridin-2-yl, 6-bromo-pyridin-3-yl, 5-bromo-pyridin-3-yl,5,6-difluoro-pyridin-3-yl, 6-chloro-pyridin-3-yl, 3-fluoro-pyridin-4-yl,5-cyano-pyridin-3-yl, pyridin-4-yl, 2-chloro-pyridin-4-yl,2-methoxy-pyridin-4-yl, 6-methyl-pyridin-3-yl, m-tolyl, thiazol-2-yl,cyclopentyl, 4-amino-pyridin-2-yl, 4-methoxy-pyridin-2-yl,4-choro-pyridin-2-yl, 4-fluoro-pyridin-2-yl, 4-cyclopropyl-pyridin-2-yl,4-bromo-pyridin-2-yl, 4-methanesulfonyl-pyridin-2-yl,4-cyano-pyridin-2-yl, hydroxymethyl, 4-oxy-pyrazin-2-yl,3-methyl-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl,5-chloro-3-fluoro-pyridin-2-yl, 3-fluoro-5-methoxy-pyridin-2-yl,2-chloro-4-fluoro-phenyl, 6-fluoro-pyridin-3-yl, 6-cyano-pyridin-3-yl,4-iodo-pyridin-2-yl, 1-oxy-pyridin-3-yl, and 4-hydroxy-pyridin-2-yl.

In some embodiments, R¹³ is selected from: 2,4-difluoro-phenyl,2,4-dichloro-phenyl, 2-fluoro-4-methanesulfonyl-phenyl,2,6-difluoro-phenyl, 2,5-difluoro-phenyl, 4-methoxy-phenyl,4-cyano-phenyl, 4-fluoro-phenyl, phenyl, 2-fluoro-phenyl,3-fluoro-phenyl, o-tolyl, tert-butyl, isopropyl, 2,2-dimethylpropyl,hydroxyl, 2-hydroxy-2-methylpropyl, 1-oxo-hexahydro-1λ⁴-thiopyran-4-yl,1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl, tetrahydrothiopyran-4-yl,morpholin-4-yl, tetrahydro-pyran-4-yl,1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl, pyrazin-2-yl,5-ethyl-pyrazin-2-yl, 5-hydroxy-pyrazin-2-yl, 5-isopropyl-pyrazin-2-yl,5-heptafluoropropyl-pyrazin-2-yl, 5-cyclobutyl-pyrazin-2-yl,5-methyl-pyrazin-2-yl, 6-ethyl-pyrazin-2-yl,5-trifluoromethyl-pyrazin-2-yl, cyclopropyl, 5-cyclopropyl-pyrazin-2-yl,6-chloro-pyrazin-2-yl, 5-dimethylamino-pyrazin-2-yl, 4-cyano-phenyl,6-methoxy-pyridazin-3-yl, 6-chloro-pyridazin-3-yl, pyrimidin-5-yl,6-dimethylamino-pyrazin-2-yl, 6-methoxy-pyrazin-2-yl, 2-pyrimidin-4-yl,5-bromo-pyrazin-2-yl, 5-hydroxy-pyrazin-2-yl, 5-methoxy-pyrazin-2-yl,5-ethoxypyrazin-2-yl, 5-methylamino-pyrazin-2-yl, 5-bromo-pyridin-2-yl,pyridin-3-yl, 5-trifluoromethyl-pyridin-2-yl, 5-isopropyl-pyridin-2-yl,5-isopropyl-pyridin-2-yl, 5-methyl-pyridin-2-yl, 5-ethyl-pyridin-2-yl,5-methoxy-pyridin-2-yl, 4-trifluoromethyl-pyridin-2-yl,5-cyano-pyridin-2-yl, 5-dimethylamino-pyridin-2-yl,4-methyl-pyridin-2-yl, 5-chloro-4-methyl-pyridin-2-yl,5-chloro-4-trifluoromethyl-pyridin-2-yl, 4-trifluoromethyl-pyridin-2-yl,3-fluoro-pyridin-2-yl, 6-methyl-4-trifluoromethyl-pyridin-2-yl,3-methyl-pyridin-2-yl, 5-propyl-pyridin-2-yl,5-cyclopropyl-pyridin-2-yl, 5-fluoro-pyridin-2-yl,3,5-difluoro-pyridin-2-yl, 6-bromo-pyridin-3-yl, 5-bromo-pyridin-3-yl,5,6-difluoro-pyridin-3-yl, 6-chloro-pyridin-3-yl, 3-fluoro-pyridin-4-yl,5-cyano-pyridin-3-yl, pyridin-4-yl, 2-chloro-pyridin-4-yl,2-methoxy-pyridin-4-yl, 6-methyl-pyridin-3-yl, m-tolyl, thiazol-2-yl,cyclopentyl, 4-methoxy-pyridin-2-yl, 4-choro-pyridin-2-yl,4-fluoro-pyridin-2-yl, 4-cyclopropyl-pyridin-2-yl, 4-bromo-pyridin-2-yl,4-methanesulfonyl-pyridin-2-yl, 4-cyano-pyridin-2-yl, hydroxymethyl, and4-oxy-pyrazin-2-yl.

In some embodiments, R¹³ is 2,4-difluoro-phenyl. In some embodiments,R¹³ is 2,4-dichloro-phenyl. In some embodiments, R¹³ is2-fluoro-4-methanesulfonyl-phenyl. In some embodiments, R¹³ is2,6-difluoro-phenyl. In some embodiments, R¹³ is 2,5-difluoro-phenyl. Insome embodiments, R¹³ is 4-methoxy-phenyl. In some embodiments, R¹³ is4-cyano-phenyl. In some embodiments, R¹³ is 4-fluoro-phenyl. In someembodiments, R¹³ is phenyl. In some embodiments, R¹³ is 2-fluoro-phenyl.In some embodiments, R¹³ is 3-fluoro-phenyl. In some embodiments, R¹³ iso-tolyl. In some embodiments, R¹³ is tert-butyl. In some embodiments,R¹³ is isopropyl. In some embodiments, R¹³ is 2,2-dimethylpropyl. Insome embodiments, R¹³ is hydroxyl. In some embodiments, R¹³ is2-hydroxy-2-methylpropyl. In some embodiments, R¹³ is1-oxo-hexahydro-1λ⁴-thiopyran-4-yl. In some embodiments, R¹³ is1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl. In some embodiments, R¹³ istetrahydrothiopyran-4-yl. In some embodiments, R¹³ is morpholin-4-yl. Insome embodiments, R¹³ is tetrahydro-pyran-4-yl. In some embodiments, R¹³is 1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl. In some embodiments, R¹³ ispyrazin-2-yl. In some embodiments, R¹³ is 5-ethyl-pyrazin-2-yl. In someembodiments, R¹³ is 5-hydroxy-pyrazin-2-yl. In some embodiments, R¹³ is5-isopropyl-pyrazin-2-yl. In some embodiments, R¹³ is5-heptafluoropropyl-pyrazin-2-yl. In some embodiments, R¹³ is5-cyclobutyl-pyrazin-2-yl. In some embodiments, R¹³ is5-methyl-pyrazin-2-yl. In some embodiments, R¹³ is 6-ethyl-pyrazin-2-yl.In some embodiments, R¹³ is 5-trifluoromethyl-pyrazin-2-yl. In someembodiments, R¹³ is cyclopropyl. In some embodiments, R¹³ is5-cyclopropyl-pyrazin-2-yl. In some embodiments, R¹³ is6-chloro-pyrazin-2-yl. In some embodiments, R¹³ is5-dimethylamino-pyrazin-2-yl. In some embodiments, R¹³ is4-cyano-phenyl. In some embodiments, R¹³ is 6-methoxy-pyridazin-3-yl. Insome embodiments, R¹³ is 6-chloro-pyridazin-3-yl. In some embodiments,R¹³ is pyrimidin-5-yl. In some embodiments, R¹³ is6-dimethylamino-pyrazin-2-yl. In some embodiments, R¹³ is6-methoxy-pyrazin-2-yl. In some embodiments, R¹³ is 2-pyrimidin-4-yl. Insome embodiments, R¹³ is 5-bromo-pyrazin-2-yl. In some embodiments, R¹³is 5-hydroxy-pyrazin-2-yl. In some embodiments, R¹³ is5-methoxy-pyrazin-2-yl. In some embodiments, R¹³ is5-ethoxypyrazin-2-yl. In some embodiments, R¹³ is5-methylamino-pyrazin-2-yl. In some embodiments, R¹³ is5-bromo-pyridin-2-yl. In some embodiments, R¹³ is pyridin-3-yl. In someembodiments, R¹³ is 5-trifluoromethyl-pyridin-2-yl. In some embodiments,R¹³ is 5-isopropyl-pyridin-2-yl. In some embodiments, R¹³ is5-isopropyl-pyridin-2-yl. In some embodiments, R¹³ is5-methyl-pyridin-2-yl. In some embodiments, R¹³ is 5-ethyl-pyridin-2-yl.In some embodiments, R¹³ is 5-methoxy-pyridin-2-yl. In some embodiments,R¹³ is 4-trifluoromethyl-pyridin-2-yl. In some embodiments, R¹³ is5-cyano-pyridin-2-yl. In some embodiments, R¹³ is5-dimethylamino-pyridin-2-yl. In some embodiments, R¹³ is4-methyl-pyridin-2-yl. In some embodiments, R¹³ is5-chloro-4-methyl-pyridin-2-yl. In some embodiments, R¹³ is5-chloro-4-trifluoromethyl-pyridin-2-yl. In some embodiments, R¹³ is4-trifluoromethyl-pyridin-2-yl. In some embodiments, R¹³ is3-fluoro-pyridin-2-yl. In some embodiments, R¹³ is6-methyl-4-trifluoromethyl-pyridin-2-yl. In some embodiments, R¹³ is3-methyl-pyridin-2-yl. In some embodiments, R¹³ is5-propyl-pyridin-2-yl. In some embodiments, R¹³ is5-cyclopropyl-pyridin-2-yl. In some embodiments, R¹³ is5-fluoro-pyridin-2-yl. In some embodiments, R¹³ is3,5-difluoro-pyridin-2-yl. In some embodiments, R¹³ is6-bromo-pyridin-3-yl. In some embodiments, R¹³ is 5-bromo-pyridin-3-yl.In some embodiments, R¹³ is 5,6-difluoro-pyridin-3-yl. In someembodiments, R¹³ is 6-chloro-pyridin-3-yl. In some embodiments, R¹³ is3-fluoro-pyridin-4-yl. In some embodiments, R¹³ is 5-cyano-pyridin-3-yl.In some embodiments, R¹³ is pyridin-4-yl. In some embodiments, R¹³ is2-chloro-pyridin-4-yl. In some embodiments, R¹³ is2-methoxy-pyridin-4-yl. In some embodiments, R¹³ is6-methyl-pyridin-3-yl. In some embodiments, R¹³ is m-tolyl. In someembodiments, R¹³ is thiazol-2-yl. In some embodiments, R¹³ iscyclopentyl. In some embodiments, R¹³ is 4-amino-pyridin-2-yl. In someembodiments, R¹³ is 4-methoxy-pyridin-2-yl. In some embodiments, R¹³ is4-choro-pyridin-2-yl. In some embodiments, R¹³ is 4-fluoro-pyridin-2-yl.In some embodiments, R¹³ is 4-cyclopropyl-pyridin-2-yl. In someembodiments, R¹³ is 4-bromo-pyridin-2-yl. In some embodiments, R¹³ is4-methanesulfonyl-pyridin-2-yl. In some embodiments, R¹³ is4-cyano-pyridin-2-yl. In some embodiments, R¹³ is hydroxymethyl. In someembodiments, R¹³ is 4-oxy-pyrazin-2-yl. In some embodiments, R¹³ is3-methyl-1,1-dioxo-tetrahydro-116-thiophen-3-yl. In some embodiments,R¹³ is 5-chloro-3-fluoro-pyridin-2-yl. In some embodiments, R¹³ is3-fluoro-5-methoxy-pyridin-2-yl. In some embodiments, R¹³ is2-chloro-4-fluoro-phenyl. In some embodiments, R¹³ is6-fluoro-pyridin-3-yl. In some embodiments, R¹³ is 6-cyano-pyridin-3-yl.In some embodiments, R¹³ is 4-iodo-pyridin-2-yl. In some embodiments,R¹³ is 1-oxy-pyridin-3-yl. In some embodiments, R¹³ is4-hydroxy-pyridin-2-yl.

The Group R¹⁴:

In some embodiments, R¹⁴ is selected from: C₁-C₆ alkylene, C₃-C₇cycloalkenylene, C₃-C₇ cycloalkylene, heteroarylene, andheterocyclylene; wherein said C₁-C₆ alkylene and heterocyclylene areeach optionally substituted with one or more substituents selected from:C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, carboxy,heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆ alkyl andaryl are optionally substituted with one substituent selected from:C₁-C₆ alkoxyl, aryl, halogen, heteroaryl, and hydroxyl.

In some embodiments, R¹⁴ is selected from: C₁-C₆ alkylene and C₃-C₇cycloalkylene; wherein said C₁-C₆ alkylene is optionally substitutedwith one or more substituents selected from: C₁-C₆ alkyl, aryl,heterocyclyl, and hydroxyl; wherein said C₁-C₆ alkyl is optionallysubstituted with one substituent selected from: halogen, and hydroxyl.

In some embodiments, R¹⁴ is selected from: C₁-C₆ alkylene, C₃-C₇cycloalkenylene, C₃-C₇ cycloalkylene, heteroarylene, andheterocyclylene; wherein said C₁-C₆ alkylene and heterocyclylene areeach optionally substituted with one or more substituents selected from:methyl, tert-butyl, ethyl, tetrahydro-2H-pyranyl, isopropyl, benzyl,pyridinyl, hydroxymethyl, 4-fluoro-phenyl, tert-butoxycarbonyl, carboxy,methoxymethyl, hydroxyethyl, tetrahydro-furanyl, 3H-imidazolylmethyl,hydroxyl, pyrrolidiny, cyclopropyl, sec-butyl, 2,2,2-trifluoroethyl,2-fluoprpropan-2-yl, 1,1,1,3,3,3-hexafluoropropan-2-yl, andfluoromethyl.

In some embodiments, R¹⁴ is selected from: C₁-C₆ alkylene, C₃-C₇cycloalkenylene, C₃-C₇ cycloalkylene, heteroarylene, andheterocyclylene; wherein said C₁-C₆ alkylene and heterocyclylene areeach optionally substituted with one or more substituents selected from:methyl, tert-butyl, ethyl, tetrahydro-2H-pyranyl, isopropyl, benzyl,pyridinyl, hydroxymethyl, 4-fluoro-phenyl, tert-butoxycarbonyl, carboxy,methoxymethyl, hydroxyethyl, tetrahydro-furanyl, 3H-imidazolylmethyl,hydroxyl, pyrrolidinyl, and cyclopropyl.

In some embodiments, R¹⁴ is selected from: C₁-C₆ alkylene and C₃-C₇cycloalkylene; wherein said C₁-C₆ alkylene is optionally substitutedwith one or more substituents selected from: tetrahydro-2H-pyranyl,hydroxyl, 2,2,2-trifluoroethyl, and fluoromethyl.

In some embodiments, R¹⁴ is selected from: methylene, ethylene,cyclopropylene, cyclobutylene, piperidinylene, pyridinylene,tetrahydropyranylene, thiazolylene, cyclohexylene, cyclopentylene,cyclopentenylene, dioxohexahydrothiopyranylene, pyrrolidinylene,tetrahydrothiophenylene, propylene, 3,3-oxetanylene, and —SO₂—; whereinsaid ethylene, methylene, piperidinylene, propylene, and pyrrolidinyleneare each optionally substituted with one or more substituents selectedfrom: methyl, tert-butyl, ethyl, tetrahydro-2H-pyranyl, isopropyl,benzyl, pyridinyl, hydroxymethyl, 4-fluoro-phenyl, tert-butoxycarbonyl,carboxy, methoxymethyl, hydroxyethyl, tetrahydro-furanyl,3H-imidazolylmethyl, hydroxyl, pyrrolidinyl, cyclopropyl, sec-butyl,2,2,2-trifluoroethyl, 2-fluoropropan-2-yl,1,1,1,3,3,3-hexafluoropropan-2-yl, and fluoromethyl.

In some embodiments, R¹⁴ is selected from: methylene, ethylene,cyclopropylene, cyclobutylene, piperidinylene, pyridinylene,tetrahydropyranylene, thiazolylene, cyclohexylene, cyclopentylene,cyclopentenylene, dioxohexahydrothiopyranylene, pyrrolidinylene,tetrahydrothiophenylene, propylene, and —SO₂—; wherein said ethylene,methylene, piperidinylene, propylene, and pyrrolidinylene are eachoptionally substituted with one or more substituents selected from:methyl, tert-butyl, ethyl, tetrahydro-2H-pyranyl, isopropyl, benzyl,pyridinyl, hydroxymethyl, 4-fluoro-phenyl, tert-butoxycarbonyl, carboxy,methoxymethyl, hydroxyethyl, tetrahydro-furanyl, 3H-imidazolylmethyl,hydroxyl, pyrrolidinyl, and cyclopropyl.

In some embodiments, R¹⁴ is selected from: methylene, ethylene,1,1-cyclopropylene, 1,1-dimethyl-methylene, 1,1-cyclobutylene,tert-butyl-methylene, 1-methyl-4,4-piperidinylene,4,4-tetrahydro-2H-pyranylene, methyl-methylene, 1,1-cyclohexylene,1,2-cyclohexylene, 1,1-dimethyl-ethylene, 1-tert-butyl-ethylene,1-ethyl-ethylene, 1-methyl-ethylene,1-(tetrahydro-2H-pyran-4-yl)-ethylene, isopropyl-methylene,1,1-cyclopentylene, benzyl-methylene, 4,4-cyclopent-1-enylene,1,1-dioxo-hexahydro-1λ⁶-4,4-thiopyranylene,1-tert-butoxycarbonyl-4,4-piperidinylene, 1-(pyridin-4-yl)-ethylene,1-(pyridin-3-yl)-ethylene, 1-(pyridin-2-yl)-ethylene,1-(4-fluoro-phenyl)-ethylene, 1-hydroxymethyl-1-methyl-ethylene,1-carboxy-1-methyl-ethylene, 1-methoxymethyl-ethylene,1-hydroxymethyl-ethylene, 1-(1-hydroxyethyl)-ethylene,1,1-dimethyl-ethylene, 1-(tetrahydro-furan-3-yl)-ethylene,phenyl-methylene, 1-(3H-imidazol-4-ylmethyl)-ethylene,1-(4-hydroxy-phenyl)-ethylene, benzyl-ethylene,(1-hydroxymethyl-2-methyl)-ethylene, 1-isopropyl-ethylene,pyridin-2-yl-methylene, 1,1-dimethyl-propylene, 2-hydroxy-propylene,(1-isobutyl-pyrrolidin-3-yl)-methylene, 1,3-azetidinylene,1,3-pyrrolidinylene, 1,3-piperidinylene, 1,4-piperidinylene,2,4-thiazolylene, 3,4-pyridinylene, 2,4-pyridinylene, 2,5-pyridinylene,—SO₂—, 2,5-pyridinylene, 1-cyclopropyl-ethylene, 1-(sec-butyl)-ethylene,1-hydroxymethyl-1-ethyl-ethylene, 1-isopropyl-ethylene,1-(2,2,2-trifluoroethyl)-ethylene, (2-fluoropropan-2-yl)-methylene,(1,1,1,3,3,3-hexafluoropropan-2-yl)-methylene,1-(2-fluoropropan-2-yl)-ethylene, (2,2,2-trifluoroethyl)-methylene,1,1-di(fluoromethyl)-ethylene, (hydroxymethyl)(methyl)methylene,(hydroxymethyl)(methyl)methylene, 3,3-oxetanylene, and1-hydroxymethyl-1-isopropyl-ethylene.

In some embodiments, R¹⁴ is selected from: methylene, ethylene,1,1-cyclopropylene, 1,1-dimethyl-methylene, 1,1-cyclobutylene,tert-butyl-methylene, 1-methyl-4,4-piperidinylene,4,4-tetrahydro-2H-pyranylene, methyl-methylene, 1,1-cyclohexylene,1,2-cyclohexylene, 1,1-dimethyl-ethylene, 1-tert-butyl-ethylene,1-ethyl-ethylene, 1-methyl-ethylene,1-(tetrahydro-2H-pyran-4-yl)-ethylene, isopropyl-methylene,1,1-cyclopentylene, benzyl-methylene, 4,4-cyclopent-1-enylene,1,1-dioxo-hexahydro-1λ⁶-4,4-thiopyranylene,1-tert-butoxycarbonyl-4,4-piperidinylene, 1-(pyridin-4-yl)-ethylene,1-(pyridin-3-yl)-ethylene, 1-(pyridin-2-yl)-ethylene,1-(4-fluoro-phenyl)-ethylene, 1-hydroxymethyl-1-methyl-ethylene,1-carboxy-1-methyl-ethylene, 1-methoxymethyl-ethylene,1-hydroxymethyl-ethylene, 1-(1-hydroxyethyl)-ethylene,1,1-dimethyl-ethylene, 1-(tetrahydro-furan-3-yl)-ethylene,phenyl-methylene, 1-(3H-imidazol-4-ylmethyl)-ethylene,1-(4-hydroxy-phenyl)-ethylene, benzyl-ethylene,(1-hydroxymethyl-2-methyl)-ethylene, 1-isopropyl-ethylene,pyridin-2-yl-methylene, 1,1-dimethyl-propylene, 2-hydroxy-propylene,(1-isobutyl-pyrrolidin-3-yl)-methylene, 1,3-azetidinylene,1,3-pyrrolidinylene, 1,3-piperidinylene, 1,4-piperidinylene,2,4-thiazolylene, 3,4-pyridinylene, 2,4-pyridinylene, 2,5-pyridinylene,—SO₂—, 2,5-pyridinylene, and 1-cyclopropyl-ethylene.

In some embodiments, R¹⁴ is selected from: 1,1-cyclopropylene,1,1-dimethyl-methylene, 1,1-cyclobutylene, tert-butyl-methylene,1,1-dimethyl-ethylene, 1-tert-butyl-ethylene,1-(tetrahydro-2H-pyran-4-yl)-ethylene, isopropyl-methylene,1-hydroxymethyl-1-methyl-ethylene, phenyl-methylene,1-isopropyl-ethylene, 1-(2,2,2-trifluoroethyl)-ethylene, and1,1-di(fluoromethyl)-ethylene.

In some embodiments, R¹⁴ is methylene. In some embodiments, R¹⁴ isethylene. In some embodiments, R¹⁴ is 1,1-cyclopropylene. In someembodiments, R¹⁴ is 1,1-dimethyl-methylene. In some embodiments, R¹⁴ is1,1-cyclobutylene. In some embodiments, R¹⁴ is tert-butyl-methylene. Insome embodiments, R¹⁴ is 1-methyl-4,4-piperidinylene. In someembodiments, R¹⁴ is 4,4-tetrahydro-2H-pyranylene. In some embodiments,R¹⁴ is methyl-methylene. In some embodiments, R¹⁴ is 1,1-cyclohexylene.In some embodiments, R¹⁴ is 1,2-cyclohexylene. In some embodiments, R¹⁴is 1,1-dimethyl-ethylene. In some embodiments, R¹⁴ is1-tert-butyl-ethylene. In some embodiments, R¹⁴ is 1-ethyl-ethylene. Insome embodiments, R¹⁴ is 1-methyl-ethylene. In some embodiments, R¹⁴ is1-(tetrahydro-2H-pyran-4-yl)-ethylene. In some embodiments, R¹⁴ isisopropyl-methylene. In some embodiments, R¹⁴ is 1,1-cyclopentylene. Insome embodiments, R¹⁴ is benzyl-methylene. In some embodiments, R¹⁴ is4,4-cyclopent-1-enylene. In some embodiments, R¹⁴ is1,1-dioxo-hexahydro-1λ⁶-4,4-thiopyranylene. In some embodiments, R¹⁴ is1-tert-butoxycarbonyl-4,4-piperidinylene. In some embodiments, R¹⁴ is1-(pyridin-4-yl)-ethylene. In some embodiments, R¹⁴ is1-(pyridin-3-yl)-ethylene. In some embodiments, R¹⁴ is1-(pyridin-2-yl)-ethylene. In some embodiments, R¹⁴ is1-(4-fluoro-phenyl)-ethylene. In some embodiments, R¹⁴ is1-hydroxymethyl-1-methyl-ethylene. In some embodiments, R¹⁴ is1-carboxy-1-methyl-ethylene. In some embodiments, R¹⁴ is1-methoxymethyl-ethylene. In some embodiments, R¹⁴ is1-hydroxymethyl-ethylene. In some embodiments, R¹⁴ is1-(1-hydroxyethyl)-ethylene. In some embodiments, R¹⁴ is1,1-dimethyl-ethylene. In some embodiments, R¹⁴ is1-(tetrahydro-furan-3-yl)-ethylene. In some embodiments, R¹⁴ isphenyl-methylene. In some embodiments, R¹⁴ is1-(3H-imidazol-4-ylmethyl)-ethylene. In some embodiments, R¹⁴ is1-(4-hydroxy-phenyl)-ethylene. In some embodiments, R¹⁴ isbenzyl-ethylene. In some embodiments, R¹⁴ is(1-hydroxymethyl-2-methyl)-ethylene. In some embodiments, R¹⁴ is1-isopropyl-ethylene. In some embodiments, R¹⁴ ispyridin-2-yl-methylene. In some embodiments, R¹⁴ is1,1-dimethyl-propylene. In some embodiments, R¹⁴ is 2-hydroxy-propylene.In some embodiments, R¹⁴ is (1-isobutyl-pyrrolidin-3-yl)-methylene. Insome embodiments, R¹⁴ is 1,3-azetidinylene. In some embodiments, R¹⁴ is1,3-pyrrolidinylene. In some embodiments, R¹⁴ is 1,3-piperidinylene. Insome embodiments, R¹⁴ is 1,4-piperidinylene. In some embodiments, R¹⁴ is2,4-thiazolylene. In some embodiments, R¹⁴ is 3,4-pyridinylene. In someembodiments, R¹⁴ is 2,4-pyridinylene. In some embodiments, R¹⁴ is2,5-pyridinylene. In some embodiments, R¹⁴ is —SO₂—. In someembodiments, R¹⁴ is 2,5-pyridinylene. In some embodiments, R¹⁴ is1-cyclopropyl-ethylene. In some embodiments, R¹⁴ is1-(sec-butyl)-ethylene. In some embodiments, R¹⁴ is1-hydroxymethyl-1-ethyl-ethylene. In some embodiments, R¹⁴ is1-isopropyl-ethylene. In some embodiments, R¹⁴ is1-(2,2,2-trifluoroethyl)-ethylene. In some embodiments, R¹⁴ is(2-fluoropropan-2-yl)-methylene. In some embodiments, R¹⁴ is(1,1,1,3,3,3-hexafluoropropan-2-yl)-methylene. In some embodiments, R¹⁴is 1-(2-fluoropropan-2-yl)-ethylene. In some embodiments, R¹⁴ is(2,2,2-trifluoroethyl)-methylene. In some embodiments, R¹⁴ is1,1-di(fluoromethyl)-ethylene. In some embodiments, R¹⁴ is(hydroxymethyl)(methyl)methylene. In some embodiments, R¹⁴ is(hydroxymethyl)(methyl)methylene. In some embodiments, R¹⁴ is3,3-oxetanylene. In some embodiments, R¹⁴ is1-hydroxymethyl-1-isopropyl-ethylene.

In some embodiments, R¹⁴ is absent.

The Group R¹⁵:

In some embodiments, R¹⁵ is selected from: —C(O)NH—, —C(O)—, —C(O)O—,C₁-C₆ alkylene, C₃-C₇ cycloalkylene, heteroarylene, and heterocyclylene;wherein said heterocyclylene is optionally substituted with C₁-C₆ alkyl.

In some embodiments, R¹⁵ is selected from: —C(O)NH—, —C(O)—, C₁-C₆alkylene, C₃-C₇ cycloalkylene, heteroarylene, and heterocyclylene;wherein said heterocyclylene is optionally substituted with C₁-C₆ alkyl.

In some embodiments, R¹⁵ is selected from: —C(O)NH—, —C(O)—, —C(O)O—,C₁-C₆ alkylene, C₃-C₇ cycloalkylene, heteroarylene, and heterocyclylene;wherein said heterocyclylene is optionally substituted with methyl.

In some embodiments, R¹⁵ is selected from: —C(O)NH—, —C(O)—, C₁-C₆alkylene, C₃-C₇ cycloalkylene, heteroarylene, and heterocyclylene;wherein said heterocyclylene is optionally substituted with methyl.

In some embodiments, R¹⁵ is selected from: pyrrolidinylene,piperidinylene, pyridinylene, azetidinylene, —C(O)NH—, —C(O)—, —C(O)O—,morpholinylene, methylene, ethylene, cyclopropylene,tetrahydropyranylene, cyclopentylene, tetrahydrothiophenylene,oxotetrahydrothiophenylene; wherein said piperidinylene is optionallysubstituted with methyl.

In some embodiments, R¹⁵ is selected from: pyrrolidinylene,piperidinylene, pyridinylene, azetidinylene, —C(O)NH—, —C(O)—,morpholinylene, methylene, ethylene, cyclopropylene,tetrahydropyranylene, cyclopentylene, tetrahydrothiophenylene,oxotetrahydrothiophenylene; wherein said piperidinylene is optionallysubstituted with methyl.

In some embodiments, R¹⁵ is selected from: 1,3-pyrrolidinylene,1,4-piperidinylene, 2,6-pyridinylene, 1,3-azetidinylene, —C(O)NH—,—C(O)—, —C(O)O—, 1,2-pyrrolidinylene, 2,4-morpholinylene, ethylene,methylene, 1,1-cyclopentylene, 4,4-tetrahydro-2H-pyranylene,3,3-tetrahydro-thiophenylene, 1,1-cyclopropylene,1-methyl-4,4-piperidinylene, and 1-oxo-tetrahydro-1λ⁴-3,3-thiophenylene.

In some embodiments, R¹⁵ is selected from: 1,3-pyrrolidinylene,1,4-piperidinylene, 2,6-pyridinylene, 1,3-azetidinylene, —C(O)NH—,—C(O)—, 1,2-pyrrolidinylene, 2,4-morpholinylene, ethylene, methylene,1,1-cyclopentylene, 4,4-tetrahydro-2H-pyranylene,3,3-tetrahydro-thiophenylene, 1,1-cyclopropylene,1-methyl-4,4-piperidinylene, and 1-oxo-tetrahydro-1λ⁴-3,3-thiophenylene.

In some embodiments, R¹⁵ is selected from: —C(O)NH— and —C(O)O—.

In some embodiments, R¹⁵ is 1,3-pyrrolidinylene. In some embodiments,R¹⁵ is 1,4-piperidinylene. In some embodiments, R¹⁵ is 2,6-pyridinylene.In some embodiments, R¹⁵ is 1,3-azetidinylene. In some embodiments, R¹⁵is —C(O)NH—. In some embodiments, R¹⁵ is —C(O)—. In some embodiments,R¹⁵ is 1,2-pyrrolidinylene. In some embodiments, R¹⁵ is2,4-morpholinylene. In some embodiments, R¹⁵ is ethylene. In someembodiments, R¹⁵ is methylene. In some embodiments, R¹⁵ is1,1-cyclopentylene. In some embodiments, R¹⁵ is4,4-tetrahydro-2H-pyranylene. In some embodiments, R¹⁵ is3,3-tetrahydro-thiophenylene. In some embodiments, R¹⁵ is1,1-cyclopropylene. In some embodiments, R¹⁵ is1-methyl-4,4-piperidinylene. In some embodiments, R¹⁵ is1-oxo-tetrahydro-1λ⁴-3,3-thiophenylene.

In some embodiments, R¹⁵ is absent.

The Group R¹⁶:

In some embodiments, R¹⁶ is C₁-C₆ alkylene.

In some embodiments, R¹⁶ is selected from: ethylene, methylene,isopropyl-methylene, and propylene.

In some embodiments, R¹⁶ is selected from: methylene,isopropyl-methylene, and propylene.

In some embodiments, R¹⁶ is selected from: ethylene, and methylene.

In some embodiments, R¹⁶ is ethylene.

In some embodiments, R¹⁶ is methylene.

In some embodiments, R¹⁶ is absent.

The Group R¹⁷:

In some embodiments, R¹⁷ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl,C₁-C₆ alkylamino, C₁-C₆ alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino,aryl, arylamino, arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy, carboxamide,carboxy, cyano, C₃-C₇ cycloalkyl, C₅-C₁₁ bicycloalkyl, C₃-C₇cycloalkylamino, C₂-C₈ dialkylamino, C₂-C₈ dialkylsulfonamide, C₁-C₆haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl,hydroxyl, and phosphonooxy; wherein said C₁-C₆ alkylamino, aryl,arylamino, aryloxy, C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkyl, heteroaryl,heterobicyclyl, heterocyclyl, and ureyl are each optionally substitutedwith one or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, amino, aryl, carboxy,cyano, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈ dialkylamino,C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen, heteroaryl, heterocyclyl,and hydroxyl.

In some embodiments, R¹⁷ is selected from: H, C₁-C₆ alkyl, C₁-C₆alkylamino, amino, aryl, carboxy, cyano, C₁-C₆ haloalkyl, heteroaryl,hydroxyl, and phosphonooxy; wherein said aryl is optionally substitutedwith one hydroxyl group.

In some embodiments, R¹⁷ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl,C₁-C₆ alkylamino, C₁-C₆ alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino,aryl, arylamino, arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy, carboxamide,carboxy, cyano, C₃-C₇ cycloalkyl, C₅-C₁₁ bicycloalkyl, C₃-C₇cycloalkylamino, C₂-C₈ dialkylamino, C₂-C₈ dialkylsulfonamide, C₁-C₆haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl,hydroxyl, and phosphonooxy; wherein said C₁-C₆ alkylamino, amino, aryl,arylamino, aryloxy, C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkylamino, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl areeach optionally substituted with one or more substituents selected from:amino, tert-butoxycarbonylamino, methyl, tert-butoxycarbonyl, ethyl,hydroxyl, isopropyl, tert-butyl, fluoro, chloro, methoxy,methanesulfonyl, carboxy, trifluoromethoxy, difluoromethoxy,dimethylamino, methoxycarbonyl, ethoxycarbonyl, carboxy, carboxamide,trifluoromethyl, diethylamino, cyano, tert-butylamino, cyclopropyl,cyclobutyl, phenyl, bromo, 1-methyl-pyrrolidinyl, 2,2,2-trifluoroethyl,and 1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl.

In some embodiments, R¹⁷ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl,C₁-C₆ alkylamino, C₁-C₆ alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino,aryl, arylamino, arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy, carboxamide,carboxy, cyano, C₃-C₇ cycloalkyl, C₅-C₁₁ bicycloalkyl, C₃-C₇cycloalkylamino, C₂-C₈ dialkylamino, C₂-C₈ dialkylsulfonamide, C₁-C₆haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl,hydroxyl, and phosphonooxy; wherein said C₁-C₆ alkylamino, aryl,arylamino, aryloxy, C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkylamino, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl areeach optionally substituted with one or more substituents selected from:amino, 1-tert-butoxycarbonylamino, methyl, 1-tert-butoxycarbonyl, ethyl,hydroxyl, isopropyl, tert-butyl, fluoro, chloro, methoxy,methanesulfonyl, carboxy, trifluoromethoxy, difluoromethoxy,dimethylamino, methoxycarbonyl, ethoxycarbonyl, carboxy, carboxamide,trifluoromethyl, diethylamino, cyano, tert-butylamino, cyclopropyl,cyclobutyl, phenyl, bromo, and 1-methyl-pyrrolidinyl.

In some embodiments, R¹⁷ is selected from: H, C₁-C₆ alkyl, C₁-C₆alkylamino, amino, aryl, carboxy, cyano, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, heteroaryl, heterocyclyl, hydroxyl, and phosphonooxy; whereinsaid aryl and C₃-C₇ cycloalkyl are each optionally substituted with oneor more substituents selected from: hydroxyl and trifluoromethyl.

In some embodiments, R¹⁷ is selected from: H, amino,1-tert-butoxycarbonylamino, morpholin-4-yl, 4-methyl-piperidin-1-yl,piperidin-4-yl, 1-tert-butoxycarbonyl-piperidin-3-yl,tetrahydro-thiopyran-4-yl, 1-oxo-hexahydro-1λ⁴-thiopyran-4-yl,tetrahydro-pyran-4-yl, pyrrolidin-1-yl,1-tert-butoxycarbonyl-azetidin-3-yl, 2,6-dimethyl-morpholin-4-yl,piperidin-1-yl, 1-tert-butoxycarbonyl-piperidin-4-yl,1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl, tetrahydro-furan-2-yl,1-ethyl-pyrrolidin-2-yl, 1-methyl-pyrrolidin-2-yl, morpholin-2-yl,1-methyl-piperidin-2-yl, 1-methyl-piperidin-4-yl,4-hydroxy-1-methyl-piperidin-4-yl, thiomorpholin-4-yl,tetrahydro-furan-3-yl, 1-tert-butoxycarbonyl-pyrrolidin-4-yl,1,2,2,6,6-pentamethyl-piperidin-4-yl,1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl, 4-methyl-morpholin-2-yl,4-tert-butoxycarbonyl-morpholin-2-yl, 1-isopropyl-piperidin-4-yl,4-hydroxy-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl,3-methyl-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl, phenyl,2-hydroxy-indan-1-yl, indan-1-yl, cyclopentyl, 2-hydroxy-cyclopentyl,cyclobutyl, 2-hydroxy-cyclohexyl,1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl,6,6-dimethyl-bicyclo[3.1.1]hept-2-yl, 1-aza-bicyclo[2.2.2]oct-3-yl,9-methyl-9-aza-bicyclo[3.3.1]non-1-yl, 3-azepan-1-yl, 2-fluoro-phenyl,2-chloro-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 3-fluoro-phenyl,5-fluoro-2-methoxy-phenyl, 2-fluoro-4-methanesulfonyl-phenyl,4-carboxy-2-fluoro-phenyl, 2,5-difluoro-phenyl, m-tolyl, o-tolyl,2,5-dimethyl-phenyl, 2,3-dimethyl-phenyl, 4-hydroxy-3-methoxy-phenyl,2,4-dimethoxy-phenyl, 2,3-dimethoxy-phenyl, 3,5-dimethoxy-phenyl,4-methoxy-phenyl, 3-methoxy-phenyl, 2-methoxy-phenyl, 3-hydroxy-phenyl,4-hydroxy-phenyl, 2-hydroxy-phenyl, 5-fluoro-2-hydroxy-phenyl,3-trifluoromethoxy-phenyl, 4-difluoromethoxy-phenyl,3-difluoromethoxy-phenyl, 4-fluoro-phenoxy, 2-dimethylamino-phenyl,4-dimethylamino-phenyl, 6-fluoro-4H-benzo[1,3]dioxin-8-yl,benzo[1,3]dioxol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl,2,6-dimethyl-pyrimidin-4-yl, pyridazin-3-yl, 5-methyl-pyrazin-2-yl,6-methoxy-pyrimidin-4-yl, pyrazin-2-yl, 3,5-dimethyl-pyrazin-2-yl,5-fluoro-2-oxo-2,3-dihydro-pyrimidin-4-yl, hydroxyl, methoxycarbonyl,ethoxycarbonyl, carboxy, 1-piperidin-1-yl, carboxamide, methoxy,trifluoromethyl, methyl, tert-butyl, diethylamino, dimethylamino, cyano,tert-butylamino, cyclopropyl, pyridin-3-yloxy, 1H-tetrazol-5-yl,5-methyl-[1,2,4]oxadiazol-3-yl, phosphonooxy, cyclobutylamino,phenylamino, 1-tert-butyl-3-methylureido, 3-methyl-1-phenylureido,N-tert-butylmethylsulfonamido, 1-cyclobutyl-3-methylureido,methylcarbamoyl, 5-hydroxy-1H-indol-3-yl, 1H-benzoimidazol-2-yl,5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl, 1H-benzoimidazol-2-yl,2-(tert-butoxycarbonyl)-3,4-dihydro-1H-isoquinoline-2-yl, quinolin-3-yl,quinolin-4-yl, 2-methyl-quinolin-4-yl, benzooxazol-2-yl,1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl, 2,3-dihydro-benzofuran-3-yl,benzothiazol-2-yl, 1,4-dimethyl-1H-pyrrol-2-yl,3-methyl-3H-imidazol-4-yl, 1H-imidazol-4-yl, 5-hydroxy-1H-pyrazol-3-yl,1-methyl-1H-pyrazol-3-yl, 4-pyridin-2-yl-thiazol-2-yl,5-methyl-thiazol-2-yl, oxazol-4-yl, 4-phenyl-thiazol-2-yl,5-tert-butyl-isoxazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,3-hydroxy-pyridin-2-yl, 6-hydroxy-pyridin-3-yl, 3-hydroxy-pyridin-4-yl,4-hydroxy-pyridin-2-yl, 6-hydroxy-pyridin-2-yl, 2-hydroxy-pyridin-3-yl,2-methoxy-pyridin-3-yl, 5-methoxy-pyridin-2-yl, 4-methoxy-pyridin-2-yl,2-methoxy-pyridin-4-yl, 6-methoxy-pyridin-2-yl, 6-methoxy-pyridin-3-yl,3-fluoro-pyridin-2-yl, 2-fluoro-pyridin-3-yl, 6-fluoro-pyridin-2-yl,5-fluoro-pyridin-2-yl, 6-fluoro-pyridin-3-yl, 3-fluoro-pyridin-4-yl,3-methyl-pyridin-2-yl, 3-methyl-pyridin-4-yl, 6-methyl-pyridin-2-yl,4-methyl-pyridin-2-yl, 6-methyl-pyridin-3-yl, 2-methyl-pyridin-3-yl,5-trifluoromethyl-pyridin-2-yl, 6-trifluoromethyl-pyridin-3-yl,4-trifluoromethyl-pyridin-2-yl, 3-chloro-5-trifluoromethyl-pyridin-2-yl,4,6-dimethyl-pyridin-2-yl, 4,6-dimethyl-pyridin-2-yl,3-chloro-5-methyl-pyridin-2-yl, 6-cyano-pyridin-3-yl,3-cyano-5-methyl-pyridin-2-yl, 3-cyano-5-methyl-pyridin-2-yl,3-chloro-5-methyl-pyridin-2-yl, 2-chloro-pyridin-3-yl,5-chloro-pyridin-2-yl, 6-chloro-2-methyl-pyridin-3-yl,6-chloro-pyridin-3-yl, 3-chloro-pyridin-4-yl,6-bromo-2-methyl-pyridin-3-yl, 5-bromo-3-methyl-pyridin-2-yl,6-carboxypyridin-2-yl, 6-methanesulfonyl-4-methyl-pyridin-3-yl,6-methanesulfonyl-4-methyl-pyridin-3-yl,6-methanesulfonyl-2-methyl-pyridin-3-yl, 6-methanesulfonyl-pyridin-3-yl,2,6-dimethoxy-pyridin-3-yl, 5-fluoro-1-oxy-pyridin-2-yl,1-oxy-pyridin-2-yl, 6-pyrrolidin-1-yl-pyridin-2-ylmethyl,5-(1-methyl-pyrrolidin-2-yl)-pyridin-2-yl,6-morpholin-4-yl-pyridin-2-yl, 6-morpholin-4-yl-pyridin-3-yl, ethynyl,tert-butyl(methyl)amino, 2,2,2-trifluoroethyl,N-cyclobutylmethylsulfonamido, N-phenylmethylsulfonamido,hydroxy(methyl)amino, methoxy(methyl)amino, azetidin-1-yl, tert-butoxy,fluoromethyl, 2,2,2-trifluoroethylamino, and(1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl)amino.

In some embodiments, R¹⁷ is selected from: H, amino,1-tert-butoxycarbonylamino, morpholin-4-yl, 4-methyl-piperidin-1-yl,piperidin-4-yl, 1-tert-butoxycarbonyl-piperidin-3-yl,tetrahydro-thiopyran-4-yl, 1-oxo-hexahydro-1λ⁴-thiopyran-4-yl,tetrahydro-pyran-4-yl, pyrrolidin-1-yl,1-tert-butoxycarbonyl-azetidin-3-yl, 2,6-dimethyl-morpholin-4-yl,piperidin-1-yl, 1-tert-butoxycarbonyl-piperidin-4-yl,1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl, tetrahydro-furan-2-yl,1-ethyl-pyrrolidin-2-yl, 1-methyl-pyrrolidin-2-yl, morpholin-2-yl,1-methyl-piperidin-2-yl, 1-methyl-piperidin-4-yl,4-hydroxy-1-methyl-piperidin-4-yl, thiomorpholin-4-yl,tetrahydro-furan-3-yl, 1-tert-butoxycarbonyl-pyrrolidin-4-yl,1,2,2,6,6-pentamethyl-piperidin-4-yl,1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl, 4-methyl-morpholin-2-yl,4-tert-butoxycarbonyl-morpholin-2-yl, 1-isopropyl-piperidin-4-yl,4-hydroxy-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl,3-methyl-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl, phenyl,2-hydroxy-indan-1-yl, indan-1-yl, cyclopentyl, 2-hydroxy-cyclopentyl,cyclobutyl, 2-hydroxy-cyclohexyl,1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl,6,6-dimethyl-bicyclo[3.1.1]hept-2-yl, 1-aza-bicyclo[2.2.2]oct-3-yl,9-methyl-9-aza-bicyclo[3.3.1]non-1-yl, 3-azepan-1-yl, 2-fluoro-phenyl,2-chloro-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 3-fluoro-phenyl,5-fluoro-2-methoxy-phenyl, 2-fluoro-4-methanesulfonyl-phenyl,4-carboxy-2-fluoro-phenyl, 2,5-difluoro-phenyl, m-tolyl, o-tolyl,2,5-dimethyl-phenyl, 2,3-dimethyl-phenyl, 4-hydroxy-3-methoxy-phenyl,2,4-dimethoxy-phenyl, 2,3-dimethoxy-phenyl, 3,5-dimethoxy-phenyl,4-methoxy-phenyl, 3-methoxy-phenyl, 2-methoxy-phenyl, 3-hydroxy-phenyl,4-hydroxy-phenyl, 2-hydroxy-phenyl, 5-fluoro-2-hydroxy-phenyl,3-trifluoromethoxy-phenyl, 4-difluoromethoxy-phenyl,3-difluoromethoxy-phenyl, 4-fluoro-phenoxy, 2-dimethylamino-phenyl,4-dimethylamino-phenyl, 6-fluoro-4H-benzo[1,3]dioxin-8-yl,benzo[1,3]dioxol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl,2,6-dimethyl-pyrimidin-4-yl, pyridazin-3-yl, 5-methyl-pyrazin-2-yl,6-methoxy-pyrimidin-4-yl, pyrazin-2-yl, 3,5-dimethyl-pyrazin-2-yl,5-fluoro-2-oxo-2,3-dihydro-pyrimidin-4-yl, hydroxyl, methoxycarbonyl,ethoxycarbonyl, carboxy, 1-piperidin-1-yl, carboxamide, methoxy,trifluoromethyl, methyl, tert-butyl, diethylamino, dimethylamino, cyano,tert-butylamino, cyclopropyl, pyridin-3-yloxy, 1H-tetrazol-5-yl,5-methyl-[1,2,4]oxadiazol-3-yl, phosphonooxy, cyclobutylamino,phenylamino, 1-tert-butyl-3-methylureido, 3-methyl-1-phenylureido,N-tert-butylmethylsulfonamido, 1-cyclobutyl-3-methylureido,methylcarbamoyl, 5-hydroxy-1H-indol-3-yl, 1H-benzoimidazol-2-yl,5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl, 1H-benzoimidazol-2-yl,2-(tert-butoxycarbonyl)-3,4-dihydro-1H-isoquinoline-2-yl, quinolin-3-yl,quinolin-4-yl, 2-methyl-quinolin-4-yl, benzooxazol-2-yl,1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl, 2,3-dihydro-benzofuran-3-yl,benzothiazol-2-yl, 1,4-dimethyl-1H-pyrrol-2-yl,3-methyl-3H-imidazol-4-yl, 1H-imidazol-4-yl, 5-hydroxy-1H-pyrazol-3-yl,1-methyl-1H-pyrazol-3-yl, 4-pyridin-2-yl-thiazol-2-yl,5-methyl-thiazol-2-yl, oxazol-4-yl, 4-phenyl-thiazol-2-yl,5-tert-butyl-isoxazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,3-hydroxy-pyridin-2-yl, 6-hydroxy-pyridin-3-yl, 3-hydroxy-pyridin-4-yl,4-hydroxy-pyridin-2-yl, 6-hydroxy-pyridin-2-yl, 2-hydroxy-pyridin-3-yl,2-methoxy-pyridin-3-yl, 5-methoxy-pyridin-2-yl, 4-methoxy-pyridin-2-yl,2-methoxy-pyridin-4-yl, 6-methoxy-pyridin-2-yl, 6-methoxy-pyridin-3-yl,3-fluoro-pyridin-2-yl, 2-fluoro-pyridin-3-yl, 6-fluoro-pyridin-2-yl,5-fluoro-pyridin-2-yl, 6-fluoro-pyridin-3-yl, 3-fluoro-pyridin-4-yl,3-methyl-pyridin-2-yl, 3-methyl-pyridin-4-yl, 6-methyl-pyridin-2-yl,4-methyl-pyridin-2-yl, 6-methyl-pyridin-3-yl, 2-methyl-pyridin-3-yl,5-trifluoromethyl-pyridin-2-yl, 6-trifluoromethyl-pyridin-3-yl,4-trifluoromethyl-pyridin-2-yl, 3-chloro-5-trifluoromethyl-pyridin-2-yl,4,6-dimethyl-pyridin-2-yl, 4,6-dimethyl-pyridin-2-yl,3-chloro-5-methyl-pyridin-2-yl, 6-cyano-pyridin-3-yl,3-cyano-5-methyl-pyridin-2-yl, 3-cyano-5-methyl-pyridin-2-yl,3-chloro-5-methyl-pyridin-2-yl, 2-chloro-pyridin-3-yl,5-chloro-pyridin-2-yl, 6-chloro-2-methyl-pyridin-3-yl,6-chloro-pyridin-3-yl, 3-chloro-pyridin-4-yl,6-bromo-2-methyl-pyridin-3-yl, 5-bromo-3-methyl-pyridin-2-yl,6-carboxypyridin-2-yl, 6-methanesulfonyl-4-methyl-pyridin-3-yl,6-methanesulfonyl-4-methyl-pyridin-3-yl,6-methanesulfonyl-2-methyl-pyridin-3-yl, 6-methanesulfonyl-pyridin-3-yl,2,6-dimethoxy-pyridin-3-yl, 5-fluoro-1-oxy-pyridin-2-yl,1-oxy-pyridin-2-yl, 6-pyrrolidin-1-yl-pyridin-2-ylmethyl,5-(1-methyl-pyrrolidin-2-yl)-pyridin-2-yl,6-morpholin-4-yl-pyridin-2-yl, 6-morpholin-4-yl-pyridin-3-yl, ethynyl,tert-butyl(methyl)amino, 2,2,2-trifluoroethyl,N-cyclobutylmethylsulfonamido, N-phenylmethylsulfonamido,hydroxy(methyl)amino, methoxy(methyl)amino, azetidin-1-yl, andtert-butoxy.

In some embodiments, R¹⁷ is selected from: is selected from: amino,2-hydroxy-indan-1-yl, hydroxyl, carboxy, trifluoromethyl, methyl,tert-butyl, cyano, tert-butylamino, phosphonooxy, pyridin-2-yl, andfluoromethyl.

In some embodiments, R¹⁷ is H. In some embodiments, R¹⁷ is amino. Insome embodiments, R¹⁷ is 1-tert-butoxycarbonylamino. In someembodiments, R¹⁷ is morpholin-4-yl.

In some embodiments, R¹⁷ is 4-methyl-piperidin-1-yl. In someembodiments, R¹⁷ is piperidin-4-yl. In some embodiments, R¹⁷ is1-tert-butoxycarbonyl-piperidin-3-yl. In some embodiments, R¹⁷ istetrahydro-thiopyran-4-yl. In some embodiments, R¹⁷ is1-oxo-hexahydro-1λ⁴-thiopyran-4-yl. In some embodiments, R¹⁷ istetrahydro-pyran-4-yl. In some embodiments, R¹⁷ is pyrrolidin-1-yl. Insome embodiments, R¹⁷ is 1-tert-butoxycarbonyl-azetidin-3-yl. In someembodiments, R¹⁷ is 2,6-dimethyl-morpholin-4-yl. In some embodiments,R¹⁷ is piperidin-1-yl. In some embodiments, R¹⁷ is1-tert-butoxycarbonyl-piperidin-4-yl. In some embodiments, R¹⁷ is1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl. In some embodiments, R¹⁷ istetrahydro-furan-2-yl. In some embodiments, R¹⁷ is1-ethyl-pyrrolidin-2-yl. In some embodiments, R¹⁷ is1-methyl-pyrrolidin-2-yl. In some embodiments, R¹⁷ is morpholin-2-yl. Insome embodiments, R¹⁷ is 1-methyl-piperidin-2-yl. In some embodiments,R¹⁷ is 1-methyl-piperidin-4-yl. In some embodiments, R¹⁷ is4-hydroxy-1-methyl-piperidin-4-yl. In some embodiments, R¹⁷ isthiomorpholin-4-yl. In some embodiments, R¹⁷ is tetrahydro-furan-3-yl.In some embodiments, R¹⁷ is 1-tert-butoxycarbonyl-pyrrolidin-4-yl. Insome embodiments, R¹⁷ is 1,2,2,6,6-pentamethyl-piperidin-4-yl. In someembodiments, R¹⁷ is 1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl. In someembodiments, R¹⁷ is 4-methyl-morpholin-2-yl. In some embodiments, R¹⁷ is4-tert-butoxycarbonyl-morpholin-2-yl. In some embodiments, R¹⁷ is1-isopropyl-piperidin-4-yl. In some embodiments, R¹⁷ is4-hydroxy-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl. In some embodiments,R¹⁷ is 3-methyl-1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl. In someembodiments, R¹⁷ is phenyl. In some embodiments, R¹⁷ is2-hydroxy-indan-1-yl. In some embodiments, R¹⁷ is indan-1-yl. In someembodiments, R¹⁷ is cyclopentyl. In some embodiments, R¹⁷ is2-hydroxy-cyclopentyl. In some embodiments, R¹⁷ is cyclobutyl. In someembodiments, R¹⁷ is 2-hydroxy-cyclohexyl. In some embodiments, R¹⁷ is1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl. In some embodiments, R¹⁷ is6,6-dimethyl-bicyclo[3.1.1]hept-2-yl. In some embodiments, R¹⁷ is1-aza-bicyclo[2.2.2]oct-3-yl. In some embodiments, R¹⁷ is9-methyl-9-aza-bicyclo[3.3.1]non-1-yl. In some embodiments, R¹⁷ is3-azepan-1-yl. In some embodiments, R¹⁷ is 2-fluoro-phenyl. In someembodiments, R¹⁷ is 2-chloro-phenyl. In some embodiments, R¹⁷ is4-fluoro-phenyl. In some embodiments, R¹⁷ is 4-chloro-phenyl. In someembodiments, R¹⁷ is 3-fluoro-phenyl. In some embodiments, R¹⁷ is5-fluoro-2-methoxy-phenyl. In some embodiments, R¹⁷ is2-fluoro-4-methanesulfonyl-phenyl. In some embodiments, R¹⁷ is4-carboxy-2-fluoro-phenyl. In some embodiments, R¹⁷ is2,5-difluoro-phenyl. In some embodiments, R¹⁷ is m-tolyl. In someembodiments, R¹⁷ is o-tolyl. In some embodiments, R¹⁷ is2,5-dimethyl-phenyl. In some embodiments, R¹⁷ is 2,3-dimethyl-phenyl. Insome embodiments, R¹⁷ is 4-hydroxy-3-methoxy-phenyl. In someembodiments, R¹⁷ is 2,4-dimethoxy-phenyl. In some embodiments, R¹⁷ is2,3-dimethoxy-phenyl. In some embodiments, R¹⁷ is 3,5-dimethoxy-phenyl.In some embodiments, R¹⁷ is 4-methoxy-phenyl. In some embodiments, R¹⁷is 3-methoxy-phenyl. In some embodiments, R¹⁷ is 2-methoxy-phenyl. Insome embodiments, R¹⁷ is 3-hydroxy-phenyl. In some embodiments, R¹⁷ is4-hydroxy-phenyl. In some embodiments, R¹⁷ is 2-hydroxy-phenyl. In someembodiments, R¹⁷ is 5-fluoro-2-hydroxy-phenyl. In some embodiments, R¹⁷is 3-trifluoromethoxy-phenyl. In some embodiments, R¹⁷ is4-difluoromethoxy-phenyl. In some embodiments, R¹⁷ is3-difluoromethoxy-phenyl. In some embodiments, R¹⁷ is 4-fluoro-phenoxy.In some embodiments, R¹⁷ is 2-dimethylamino-phenyl. In some embodiments,R¹⁷ is 4-dimethylamino-phenyl. In some embodiments, R¹⁷ is6-fluoro-4H-benzo[1,3]dioxin-8-yl. In some embodiments, R¹⁷ isbenzo[1,3]dioxol-5-yl. In some embodiments, R¹⁷ is pyrimidin-2-yl. Insome embodiments, R¹⁷ is pyrimidin-4-yl. In some embodiments, R¹⁷ is2,6-dimethyl-pyrimidin-4-yl. In some embodiments, R¹⁷ is pyridazin-3-yl.In some embodiments, R¹⁷ is 5-methyl-pyrazin-2-yl. In some embodiments,R¹⁷ is 6-methoxy-pyrimidin-4-yl. In some embodiments, R¹⁷ ispyrazin-2-yl. In some embodiments, R¹⁷ is 3,5-dimethyl-pyrazin-2-yl. Insome embodiments, R¹⁷ is 5-fluoro-2-oxo-2,3-dihydro-pyrimidin-4-yl. Insome embodiments, R¹⁷ is hydroxyl. In some embodiments, R¹⁷ ismethoxycarbonyl. In some embodiments, R¹⁷ is ethoxycarbonyl. In someembodiments, R¹⁷ is carboxy. In some embodiments, R¹⁷ is1-piperidin-1-yl. In some embodiments, R¹⁷ is carboxamide. In someembodiments, R¹⁷ is methoxy. In some embodiments, R¹⁷ istrifluoromethyl. In some embodiments, R¹⁷ is methyl. In someembodiments, R¹⁷ is tert-butyl. In some embodiments, R¹⁷ isdiethylamino. In some embodiments, R¹⁷ is dimethylamino. In someembodiments, R¹⁷ is cyano. In some embodiments, R¹⁷ is tert-butylamino.In some embodiments, R¹⁷ is cyclopropyl. In some embodiments, R¹⁷ ispyridin-3-yloxy. In some embodiments, R¹⁷ is 1H-tetrazol-5-yl. In someembodiments, R¹⁷ is 5-methyl-[1,2,4]oxadiazol-3-yl. In some embodiments,R¹⁷ is phosphonooxy. In some embodiments, R¹⁷ is cyclobutylamino. Insome embodiments, R¹⁷ is phenylamino. In some embodiments, R¹⁷ is1-tert-butyl-3-methylureido. In some embodiments, R¹⁷ is3-methyl-1-phenylureido. In some embodiments, R¹⁷ isN-tert-butylmethylsulfonamido. In some embodiments, R¹⁷ is1-cyclobutyl-3-methylureido. In some embodiments, R¹⁷ ismethylcarbamoyl. In some embodiments, R¹⁷ is 5-hydroxy-1H-indol-3-yl. Insome embodiments, R¹⁷ is 1H-benzoimidazol-2-yl. In some embodiments, R¹⁷is 5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl. In some embodiments, R¹⁷is 1H-benzoimidazol-2-yl. In some embodiments, R¹⁷ is2-(tert-butoxycarbonyl)-3,4-dihydro-1H-isoquinoline-2-yl. In someembodiments, R¹⁷ is quinolin-3-yl. In some embodiments, R¹⁷ isquinolin-4-yl. In some embodiments, R¹⁷ is 2-methyl-quinolin-4-yl. Insome embodiments, R¹⁷ is benzooxazol-2-yl. In some embodiments, R¹⁷ is1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl. In some embodiments, R¹⁷ is2,3-dihydro-benzofuran-3-yl. In some embodiments, R¹⁷ isbenzothiazol-2-yl. In some embodiments, R¹⁷ is1,4-dimethyl-1H-pyrrol-2-yl. In some embodiments, R¹⁷ is3-methyl-3H-imidazol-4-yl. In some embodiments, R¹⁷ is 1H-imidazol-4-yl.In some embodiments, R¹⁷ is 5-hydroxy-1H-pyrazol-3-yl. In someembodiments, R¹⁷ is 1-methyl-1H-pyrazol-3-yl. In some embodiments, R¹⁷is 4-pyridin-2-yl-thiazol-2-yl. In some embodiments, R¹⁷ is5-methyl-thiazol-2-yl. In some embodiments, R¹⁷ is oxazol-4-yl. In someembodiments, R¹⁷ is 4-phenyl-thiazol-2-yl. In some embodiments, R¹⁷ is5-tert-butyl-isoxazol-3-yl. In some embodiments, R¹⁷ is pyridin-2-yl. Insome embodiments, R¹⁷ is pyridin-3-yl. In some embodiments, R¹⁷ ispyridin-4-yl. In some embodiments, R¹⁷ is 3-hydroxy-pyridin-2-yl. Insome embodiments, R¹⁷ is 6-hydroxy-pyridin-3-yl. In some embodiments,R¹⁷ is 3-hydroxy-pyridin-4-yl. In some embodiments, R¹⁷ is4-hydroxy-pyridin-2-yl. In some embodiments, R¹⁷ is6-hydroxy-pyridin-2-yl. In some embodiments, R¹⁷ is2-hydroxy-pyridin-3-yl. In some embodiments, R¹⁷ is2-methoxy-pyridin-3-yl. In some embodiments, R¹⁷ is5-methoxy-pyridin-2-yl. In some embodiments, R¹⁷ is4-methoxy-pyridin-2-yl. In some embodiments, R¹⁷ is2-methoxy-pyridin-4-yl. In some embodiments, R¹⁷ is6-methoxy-pyridin-2-yl. In some embodiments, R¹⁷ is6-methoxy-pyridin-3-yl. In some embodiments, R¹⁷ is3-fluoro-pyridin-2-yl. In some embodiments, R¹⁷ is2-fluoro-pyridin-3-yl. In some embodiments, R¹⁷ is6-fluoro-pyridin-2-yl. In some embodiments, R¹⁷ is5-fluoro-pyridin-2-yl. In some embodiments, R¹⁷ is6-fluoro-pyridin-3-yl. In some embodiments, R¹⁷ is3-fluoro-pyridin-4-yl. In some embodiments, R¹⁷ is3-methyl-pyridin-2-yl. In some embodiments, R¹⁷ is3-methyl-pyridin-4-yl. In some embodiments, R¹⁷ is6-methyl-pyridin-2-yl. In some embodiments, R¹⁷ is4-methyl-pyridin-2-yl. In some embodiments, R¹⁷ is6-methyl-pyridin-3-yl. In some embodiments, R¹⁷ is2-methyl-pyridin-3-yl. In some embodiments, R¹⁷ is5-trifluoromethyl-pyridin-2-yl. In some embodiments, R¹⁷ is6-trifluoromethyl-pyridin-3-yl. In some embodiments, R¹⁷ is4-trifluoromethyl-pyridin-2-yl. In some embodiments, R¹⁷ is3-chloro-5-trifluoromethyl-pyridin-2-yl. In some embodiments, R¹⁷ is4,6-dimethyl-pyridin-2-yl. In some embodiments, R¹⁷ is4,6-dimethyl-pyridin-2-yl. In some embodiments, R¹⁷ is3-chloro-5-methyl-pyridin-2-yl. In some embodiments, R¹⁷ is6-cyano-pyridin-3-yl. In some embodiments, R¹⁷ is3-cyano-5-methyl-pyridin-2-yl. In some embodiments, R¹⁷ is3-cyano-5-methyl-pyridin-2-yl. In some embodiments, R¹⁷ is3-chloro-5-methyl-pyridin-2-yl. In some embodiments, R¹⁷ is2-chloro-pyridin-3-yl. In some embodiments, R¹⁷ is5-chloro-pyridin-2-yl. In some embodiments, R¹⁷ is6-chloro-2-methyl-pyridin-3-yl. In some embodiments, R¹⁷ is6-chloro-pyridin-3-yl. In some embodiments, R¹⁷ is3-chloro-pyridin-4-yl. In some embodiments, R¹⁷ is6-bromo-2-methyl-pyridin-3-yl. In some embodiments, R¹⁷ is5-bromo-3-methyl-pyridin-2-yl. In some embodiments, R¹⁷ is6-carboxypyridin-2-yl. In some embodiments, R¹⁷ is6-methanesulfonyl-4-methyl-pyridin-3-yl. In some embodiments, R¹⁷ is6-methanesulfonyl-4-methyl-pyridin-3-yl. In some embodiments, R¹⁷ is6-methanesulfonyl-2-methyl-pyridin-3-yl. In some embodiments, R¹⁷ is6-methanesulfonyl-pyridin-3-yl. In some embodiments, R¹⁷ is2,6-dimethoxy-pyridin-3-yl. In some embodiments, R¹⁷ is5-fluoro-1-oxy-pyridin-2-yl. In some embodiments, R¹⁷ is1-oxy-pyridin-2-yl. In some embodiments, R¹⁷ is6-pyrrolidin-1-yl-pyridin-2-ylmethyl. In some embodiments, R¹⁷ is5-(1-methyl-pyrrolidin-2-yl)-pyridin-2-yl. In some embodiments, R¹⁷ is6-morpholin-4-yl-pyridin-2-yl. In some embodiments, R¹⁷ is6-morpholin-4-yl-pyridin-3-yl. In some embodiments, R¹⁷ is ethynyl. Insome embodiments, R¹⁷ is tert-butyl(methyl)amino. In some embodiments,R¹⁷ is 2,2,2-trifluoroethyl. In some embodiments, R¹⁷ isN-cyclobutylmethylsulfonamido. In some embodiments, R¹⁷ isN-phenylmethylsulfonamido. In some embodiments, R¹⁷ ishydroxy(methyl)amino. In some embodiments, R¹⁷ is methoxy(methyl)amino.In some embodiments, R¹⁷ is azetidin-1-yl. In some embodiments, R¹⁷ istert-butoxy. In some embodiments, R¹⁷ is fluoromethyl. In someembodiments, R¹⁷ is 2,2,2-trifluoroethylamino. In some embodiments, R¹⁷is (1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl)amino.

Certain R¹⁵ and R¹⁷ Combinations:

In some embodiments, R¹⁵ is selected from: —C(O)NH—, —C(O)—, C₁-C₆alkylene, C₃-C₇ cycloalkylene, heteroarylene, and heterocyclylene;wherein said heterocyclylene is optionally substituted with C₁-C₆ alkyl;or R¹⁵ is absent; and

R¹⁷ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino,C₁-C₆ alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino, aryl, arylamino,arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano,C₃-C₇ cycloalkyl, C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈dialkylamino, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkyl, heteroaryl,heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy;wherein said C₁-C₆ alkylamino, aryl, arylamino, aryloxy, C₅-C₁₁bicycloalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylamino, heteroaryl,heterobicyclyl, heterocyclyl, and ureyl are each optionally substitutedwith one or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, amino, aryl, carboxy,cyano, C₃-C₇ cycloalkyl, C₂-C₈ dialkylamino, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl.

Certain Combinations:

In some embodiments, R¹, R², R³, R⁴, R⁵, and R⁶ are each independentlyselected from: H and C₁-C₆ alkyl.

In some embodiments, R¹ and R⁶ are each independently selected from: H,and C₁-C₆ alkyl; and R², R³, R⁴, and R⁵ are each H.

In some embodiments, R¹, R², R³, R⁴, R⁵, and R⁶ are each independentlyselected from: H, methyl, and isopropyl.

In some embodiments, R¹ is selected from: H and methyl; R², R³, R⁴, andR⁵ are each H; and R⁶ is selected from: H and is isopropyl.

In some embodiments, R¹ is methyl; R², R³, R⁴, and R⁵ are each H; and R⁶is isopropyl.

In some embodiments, R¹, R², R³, R⁴, R⁵, and R⁶ are each H.

In some embodiments, R⁸ and R⁹ together with the nitrogen atom to whichthey are both bonded form group selected from: heterocyclyl andheterobicyclyl, each optionally substituted with one or moresubstituents selected from: carbo-C₁-C₆-alkoxy, C₁-C₆ alkoxy, C₁-C₆alkyl, aryl, carbo-C₁-C₆-alkoxy, C₁-C₆ haloalkyl, halogen, heteroaryl,heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C₁-C₆alkyl, and heteroaryl are optionally substituted with one substituentselected from: C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, halogen, and hydroxyl.

In some embodiments, R⁸ and R⁹ together with the nitrogen atom to whichthey are both bonded form 4-cyclohexylmethyl-piperazin-1-yl,hexahydro-pyrrolo[1,2-a]pyrazin-2-yl,5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl,4-methoxy-2,3-dihydro-indol-1-yl, 2-phenyl-pyrrolidin-1-yl,2-pyridin-2-yl-thiomorpholin-4-yl,2-hydroxymethyl-2,3-dihydro-indol-1-yl, 4-hydroxy-piperidin-1-yl,hexahydro-pyrrolo[1,2-a]pyrazin-2-yl,7-(methoxycarbonyl)-3,4-dihydro-1H-isoquinolin-2-yl,7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl,1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl,5-fluoro-1,3-dihydro-isoindol-2-yl,3-hydroxy-7,8-dihydro-5H-[1,6]naphthyridin-6-yl,4-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperazin-1-yl,1,3-dihydro-isoindol-2-yl,3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl,4-morpholin-4-yl-piperidin-1-yl, 3,4-dihydro-1H-isoquinolin-2-yl,4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl, 3-hydroxy-piperidin-1-yl,4-(3-chloro-phenyl)-piperazin-1-yl,6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl, morpholin-4-yl,2-hydroxymethyl-pyrrolidin-1-yl, 1,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl,3-pyridin-4-yl-pyrrolidin-1-yl, 4-(pyridin-2-yloxy)-piperidin-1-yl,3-pyridin-2-yl-pyrrolidin-1-yl,7-methyl-3,4-dihydro-2H-[1,8]naphthyridin-1-yl,3-pyridin-3-yl-pyrrolidin-1-yl, 3-hydroxy-pyrrolidin-1-yl,4-(4,6-dimethyl-pyrimidin-2-yl)-piperazin-1-yl,2-methyl-3,4-dihydro-2H-quinolin-1-yl, 2-phenyl-morpholin-4-yl orpyrazin-2-yl.

In some embodiments, R⁸ and R⁹ together with the nitrogen atom to whichthey are both bonded form 4-cyclohexylmethyl-piperazin-1-yl. In someembodiments, R⁸ and R⁹ together with the nitrogen atom to which they areboth bonded form hexahydro-pyrrolo[1,2-a]pyrazin-2-yl. In someembodiments, R⁸ and R⁹ together with the nitrogen atom to which they areboth bonded form 5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl. In someembodiments, R⁸ and R⁹ together with the nitrogen atom to which they areboth bonded form 4-methoxy-2,3-dihydro-indol-1-yl. In some embodiments,R⁸ and R⁹ together with the nitrogen atom to which they are both bondedform 2-phenyl-pyrrolidin-1-yl. In some embodiments, R⁸ and R⁹ togetherwith the nitrogen atom to which they are both bonded form2-pyridin-2-yl-thiomorpholin-4-yl. In some embodiments, R⁸ and R⁹together with the nitrogen atom to which they are both bonded form2-hydroxymethyl-2,3-dihydro-indol-1-yl. In some embodiments, R⁸ and R⁹together with the nitrogen atom to which they are both bonded form4-hydroxy-piperidin-1-yl. In some embodiments, R⁸ and R⁹ together withthe nitrogen atom to which they are both bonded formhexahydro-pyrrolo[1,2-a]pyrazin-2-yl. In some embodiments, R⁸ and R⁹together with the nitrogen atom to which they are both bonded form7-(methoxycarbonyl)-3,4-dihydro-1H-isoquinolin-2-yl. In someembodiments, R⁸ and R⁹ together with the nitrogen atom to which they areboth bonded form 7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl. In someembodiments, R⁸ and R⁹ together with the nitrogen atom to which they areboth bonded form 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl. In someembodiments, R⁸ and R⁹ together with the nitrogen atom to which they areboth bonded form 5-fluoro-1,3-dihydro-isoindol-2-yl. In someembodiments, R⁸ and R⁹ together with the nitrogen atom to which they areboth bonded form 3-hydroxy-7,8-dihydro-5H-[1,6]naphthyridin-6-yl. Insome embodiments, R⁸ and R⁹ together with the nitrogen atom to whichthey are both bonded form4-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperazin-1-yl. In someembodiments, R⁸ and R⁹ together with the nitrogen atom to which they areboth bonded form 1,3-dihydro-isoindol-2-yl. In some embodiments, R⁸ andR⁹ together with the nitrogen atom to which they are both bonded form3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl. Insome embodiments, R⁸ and R⁹ together with the nitrogen atom to whichthey are both bonded form 4-morpholin-4-yl-piperidin-1-yl. In someembodiments, R⁸ and R⁹ together with the nitrogen atom to which they areboth bonded form 3,4-dihydro-1H-isoquinolin-2-yl. In some embodiments,R⁸ and R⁹ together with the nitrogen atom to which they are both bondedform 4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl. In some embodiments, R⁸and R⁹ together with the nitrogen atom to which they are both bondedform 3-hydroxy-piperidin-1-yl. In some embodiments, R⁸ and R⁹ togetherwith the nitrogen atom to which they are both bonded form4-(3-chloro-phenyl)-piperazin-1-yl. In some embodiments, R⁸ and R⁹together with the nitrogen atom to which they are both bonded form6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl. In some embodiments, R⁸ andR⁹ together with the nitrogen atom to which they are both bonded formmorpholin-4-yl. In some embodiments, R⁸ and R⁹ together with thenitrogen atom to which they are both bonded form2-hydroxymethyl-pyrrolidin-1-yl. In some embodiments, R⁸ and R⁹ togetherwith the nitrogen atom to which they are both bonded form1,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl. In some embodiments, R⁸ and R⁹together with the nitrogen atom to which they are both bonded form3-pyridin-4-yl-pyrrolidin-1-yl. In some embodiments, R⁸ and R⁹ togetherwith the nitrogen atom to which they are both bonded form4-(pyridin-2-yloxy)-piperidin-1-yl. In some embodiments, R⁸ and R⁹together with the nitrogen atom to which they are both bonded form3-pyridin-2-yl-pyrrolidin-1-yl. In some embodiments, R⁸ and R⁹ togetherwith the nitrogen atom to which they are both bonded form7-methyl-3,4-dihydro-2H-[1,8]naphthyridin-1-yl. In some embodiments, R⁸and R⁹ together with the nitrogen atom to which they are both bondedform 3-pyridin-3-yl-pyrrolidin-1-yl. In some embodiments, R⁸ and R⁹together with the nitrogen atom to which they are both bonded form3-hydroxy-pyrrolidin-1-yl. In some embodiments, R⁸ and R⁹ together withthe nitrogen atom to which they are both bonded form4-(4,6-dimethyl-pyrimidin-2-yl)-piperazin-1-yl. In some embodiments, R⁸and R⁹ together with the nitrogen atom to which they are both bondedform 2-methyl-3,4-dihydro-2H-quinolin-1-yl. In some embodiments, R⁸ andR⁹ together with the nitrogen atom to which they are both bonded form2-phenyl-morpholin-4-yl or pyrazin-2-yl.

In some embodiments, the compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof is selectedfrom compounds of Formula Ie and pharmaceutically acceptable salts,solvates, hydrates, and N-oxides thereof:

wherein:

-   -   R⁷ is —R¹⁰—R¹¹—R¹²—R¹³; wherein:    -   R¹⁰ is selected from: C₁-C₆ alkylene, heteroarylene, and        heterocyclylene; or R¹⁰ is absent;    -   R¹¹ is selected from: —C(O)NH— and C₁-C₆ alkylene; or R¹¹ is        absent;    -   R¹² is C₁-C₆ alkylene; or R¹² is absent; and    -   R¹³ is selected from: C₁-C₆ alkyl, aryl, C₃-C₇ cycloalkyl,        heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆        alkyl, aryl, and heteroaryl are each optionally substituted with        one or two substituents selected from: C₁-C₆ alkoxy, C₁-C₆        alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, amino, C₃-C₇        cycloalkyl, cyano, C₂-C₈ dialkylamino, C₁-C₆ haloalkyl, halogen,        and hydroxyl;    -   R⁸ is —R¹⁴—R¹⁵—R¹⁶—R¹⁷; wherein:    -   R¹⁴ is selected from: C₁-C₆ alkylene, C₃-C₇ cycloalkenylene,        C₃-C₇ cycloalkylene, heteroarylene, and heterocyclylene; wherein        said C₁-C₆ alkylene and heterocyclylene are each optionally        substituted with one or more substituents selected from: C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, carboxy,        heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆ alkyl        and aryl are optionally substituted with one substituent        selected from: C₁-C₆ alkoxy, aryl, halogen, heteroaryl, and        hydroxyl; or R¹⁴ is absent;    -   R¹⁵ is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C₁-C₆ alkylene,        C₃-C₇ cycloalkylene, heteroarylene, and heterocyclylene; wherein        said heterocyclylene is optionally substituted with C₁-C₆ alkyl;        or R¹⁵ is absent;    -   R¹⁶ is C₁-C₆ alkylene; or R¹⁶ is absent; and    -   R¹⁷ is selected from: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆        alkylamino, C₁-C₆ alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino,        aryl, arylamino, arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy,        carboxamide, carboxy, cyano, C₃-C₇ cycloalkyl, C₅-C₁₁        bicycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈ dialkylamino, C₂-C₈        dialkylsulfonamide, C₁-C₆ haloalkyl, heteroaryl, heteroaryloxy,        heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy;        wherein said C₁-C₆ alkylamino, aryl, arylamino, aryloxy, C₅-C₁₁        bicycloalkyl, C₃-C₇ cycloalkyl, heteroaryl, heterobicyclyl,        heterocyclyl, and ureyl are each optionally substituted with one        or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, amino, aryl,        carboxy, cyano, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈        dialkylamino, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen,        heteroaryl, heterocyclyl, and hydroxyl; and    -   R⁹ is selected from H, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; or    -   R⁸ and R⁹ together with the nitrogen atom to which they are both        bonded form a group selected from: heterocyclyl and        heterobicyclyl, each optionally substituted with one or more        substituents selected from: carbo-C₁-C₆-alkoxy, C₁-C₆ alkoxy,        C₁-C₆ alkyl, aryl, carbo-C₁-C₆-alkoxy, C₁-C₆ haloalkyl, halogen,        heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein        said aryl, C₁-C₆ alkyl, and heteroaryl are optionally        substituted with one substituent selected from: C₃-C₇        cycloalkyl, C₁-C₆ alkoxy, halogen, and hydroxyl.

In some embodiments, the compound of Formula Ia is selected from thefollowing compounds and pharmaceutically acceptable salts, solvates,hydrates and/or N-oxides thereof:

-   Compound 151:    (1aR,5aR)-2-(5-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;-   Compound 174:    (1aR,5aR)-2-(2,4-Dichloro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-hydroxymethyl-cyclopropyl)-amide;-   Compound 264:    (1aR,5aR)-2-(5-Cyano-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;-   Compound 309:    (1aR,5aR)-2-(5-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;-   Compound 493:    (1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;-   Compound 515:    1-(2,4-Difluoro-phenyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylic    acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;-   Compound 593:    (1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid tert-butylamide;-   Compound 625:    (1aR,5aR)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (cyano-dimethyl-methyl)-amide;-   Compound 642:    (1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;-   Compound 644:    (1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;-   Compound 646: Phosphoric acid    mono-(2-{[(1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-2-methyl-propyl)    ester;-   Compound 667:    (1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid [2,2-dimethyl-1-((S)-methylcarbamoyl)-propyl]-amide;-   Compound 683: Phosphoric acid    mono-{(S)-3,3-dimethyl-2-[((1aR,5aR)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl)-amino]-butyl}ester;-   Compound 684:    (1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-2-hydroxy-1-tetrahydro-pyran-4-yl-ethyl)-amide;-   Compound 690:    (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-1-hydroxymethyl-2-methyl-propyl)-amide;-   Compound 696:    (1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;-   Compound 698:    (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-hydroxymethyl-cyclobutyl)-amide;-   Compound 699:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;-   Compound 700:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-pyridin-2-yl-cyclobutyl)-amide;-   Compound 703: Phosphoric acid    mono-((S)-3,3-dimethyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl)    ester;-   Compound 704:    (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;-   Compound 722:    (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-methylcarbamoyl-phenyl-methyl)-amide;-   Compound 746:    (S)-3,3-Dimethyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyric    acid methyl ester;-   Compound 764:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-trifluoromethyl-cyclopropyl)-amide;-   Compound 765:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-trifluoromethyl-cyclobutyl)-amide;-   Compound 766:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((R)-2,2-dimethyl-1-pyridin-2-yl-propyl)-amide;-   Compound 767:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-2,2-dimethyl-1-pyridin-2-yl-propyl)-amide;-   Compound 820:    (1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide;-   Compound 821:    (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-methyl-cyclobutyl)-amide;-   Compound 828:    (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((R)-1,2-dimethyl-propyl)-amide;-   Compound 841:    (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid [(S)-2-hydroxy-1-(tetrahydro-pyran-4-yl)-ethyl]-amide;-   Compound 844: (1aR,5aR)-Pentanedioic acid    mono-((S)-3-methyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl)    ester;-   Compound 848: (1aS,5aS)-(S)-2-Amino-3-methyl-butyric acid    (S)-3,3-dimethyl-2-{[2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl    ester;-   Compound 889:    (1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2-fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl)-amide;-   Compound 891:    (1aS,5aS)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-3,3,3-trifluoro-1-hydroxymethyl-propyl)-amide;-   Compound 896:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-1-hydroxymethyl-2-methyl-propyl)-amide;-   Compound 897:    (1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2-fluoro-1,1-dimethyl-ethyl)-amide;-   Compound 902:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid N′-tert-butyl-hydrazide;-   Compound 904:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2-fluoro-1,1-dimethyl-ethyl)-amide;-   Compound 912:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((R)-1,2-dimethyl-propyl)-amide;-   Compound 913:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-2-hydroxy-1-phenyl-ethyl)-amide;-   Compound 918:    (1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-1-fluoromethyl-2,2-dimethyl-propyl)-amide;-   Compound 919:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide;-   Compound 920:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((1S,2S)-2-hydroxy-indan-1-yl)-amide;-   Compound 921:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((1S,2R)-2-hydroxy-indan-1-yl)-amide;-   Compound 924:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-fluoromethyl-cyclobutyl)-amide;-   Compound 926:    (1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-trifluoromethyl-cyclobutyl)-amide;-   Compound 927:    (1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide;-   Compound 930:    (1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-trifluoromethyl-cyclopropyl)-amide; and-   Compound 931:    (1aR,5aR)-2-(4-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2-hydroxy-1,1-dimethyl-ethyl)-amide.

In some embodiments, the compound of Formula Ia is selected from thefollowing compounds and pharmaceutically acceptable salts, solvates,hydrates and/or N-oxides thereof:

-   Compound 699:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;-   Compound 764:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-trifluoromethyl-cyclopropyl)-amide;-   Compound 765:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-trifluoromethyl-cyclobutyl)-amide;-   Compound 919:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide;-   Compound 921:    (1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid ((1S,2R)-2-hydroxy-indan-1-yl)-amide; and-   Compound 926:    (1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic    acid (1-trifluoromethyl-cyclobutyl)-amide.

In some embodiments, the compound of Formula Ia is(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide or apharmaceutically acceptable salt, solvate, and/or hydrate, thereof.

Provided is an anhydrous form of(1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide. The physicalproperties of the crystalline form of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (anhydrous form)are summarized in the table below.

Compound 699 (Anhydrous Form) PXRD FIG. 16: Peaks of about ≧8.7%relative intensity at 8.5, 9.8, 10.7, 11.1, 11.8, 14.5, 16.5, 16.9,17.4, 18.9, 22.1, and 25.4 °2θ TGA FIG. 17: Decrease in weight of about0.24% out to about 150° C. DSC FIG. 17: Endotherm extrapolated onsettemperature: about 162° C. DMS FIG. 18: The adsorption/desorptionisotherm shows about 1.0% or less weight change from about 10% relativehumidity (RH) to about 90% RH; and about 0.1% or less weight changeafter a 10% RH to 90% RH back to 10% RH cycle, See Example 17.

Certain X-ray powder diffraction peaks for the anhydrous form of(1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide are shown in thetable below.

d-spacing Pos. [°2θ] [Å] Rel. Int. [%] 6.6 13.36534 4.4 7.9 11.2546 5.58.5 10.4588 100 9.8 9.01268 21.5 10.7 8.27929 28.3 11.1 7.94475 26.111.8 7.52225 10 13.8 6.40603 7.5 14.5 6.09847 11.3 14.9 5.95101 6 165.55637 5.8 16.5 5.37022 11.8 16.9 5.24987 26.7 17.3 5.13862 8.5 17.45.10045 14.8 18.4 4.8235 4.6 18.9 4.70416 8.7 20.2 4.40147 5.5 20.94.25028 4.4 22.1 4.01561 14.5 23.4 3.79482 3 24.7 3.60675 4.6 25.43.50373 26.6 26.5 3.36865 8.1 29.2 3.0526 2.8 29.3 3.04412 3.6

Also provided is an anhydrous crystalline form of(1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.

Also provided is an anhydrous crystalline form of(1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide having an X-raypowder diffraction pattern comprising a peak, in terms of 2θ, at8.5°±0.2°. In some embodiments, the anhydrous crystalline form has anX-ray powder diffraction pattern comprising peaks, in terms of 2θ, at8.5°±0.2°, and 10.7°±0.2°. In some embodiments, the anhydrouscrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at 8.5°±0.2°, 10.7°±0.2°, and 16.9°±0.2°. In someembodiments, the anhydrous crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at 8.5°±0.2°,10.7°±0.2°, 16.9°±0.2°, 25.4°±0.2°, and 11.1°±0.20. In some embodiments,the anhydrous crystalline form has an X-ray powder diffraction patterncomprising peaks, in terms of 2θ, at 8.5°±0.20, 10.7°±0.2°, 16.9°±0.2°,25.4°±0.2°, 11.1°±0.2°, 9.8°±0.2°, and 17.4°±0.2°. In some embodiments,the anhydrous crystalline form has an X-ray powder diffraction patterncomprising peaks, in terms of 2θ, at 8.5°±0.2°, 10.7°±0.2°, 16.9°±0.2°,25.4°±0.2°, 11.1λ°±0.2°, 9.8°±0.2°, 17.4°±0.2°, 22.1°±0.20, and16.5°±0.2°. In some embodiments, the anhydrous crystalline form has anX-ray powder diffraction pattern comprising peaks, in terms of 2θ, at8.5°±0.2°, 10.7°±0.2°, 16.9°±0.2°, 25.4°±0.2°, 11.1°±0.2°, 9.8°±0.2°,17.4°±0.2°, 22.1°±0.2°, 16.50°±0.2°, 14.5°±0.2°, 11.8±0.2°, and18.9±0.2°. In some embodiments, the anhydrous crystalline form has anX-ray powder diffraction pattern substantially as shown in FIG. 16,wherein by “substantially” is meant that the reported peaks can vary byabout ±0.2° 2θ.

In some embodiments, the anhydrous crystalline form has a differentialscanning calorimetry thermogram comprising an endotherm with anextrapolated onset temperature between about 159.6° C. and about 169.6°C. In some embodiments, the anhydrous crystalline form has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature between about 160.6° C. and about168.6° C. In some embodiments, the anhydrous crystalline form has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature between about 162.6° C. and about166.6° C. In some embodiments, the anhydrous crystalline form has havinga differential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature between about 163.6° C. and about165.6° C. In some embodiments, the anhydrous crystalline form has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature at about 164.6° C. In someembodiments, the anhydrous crystalline form has a differential scanningcalorimetry thermogram substantially as shown in FIG. 17, wherein by“substantially” is meant that the reported DSC features can vary byabout ±4° C. and that the reported DSC features can vary by about ±20joules per gram.

In some embodiments, the anhydrous crystalline form has athermogravimetric analysis profile showing about 0.5% weight loss belowabout 135° C. In some embodiments, the anhydrous crystalline form has athermogravimetric analysis profile showing about 0.25% weight loss belowabout 135° C. In some embodiments, the anhydrous crystalline form has athermogravimetric analysis profile showing about 0.05% weight loss belowabout 135° C. In some embodiments, the anhydrous crystalline form has athermogravimetric analysis profile substantially as shown in FIG. 17,wherein by “substantially” is meant that the reported TGA features canvary by about ±5° C., and that that the reported TGA features can varyby about ±2% weight change.

Also provided is an anhydrous crystalline form having:

1) an X-ray powder diffraction pattern comprising peaks, in terms of 2θ,at 8.5°±0.2°, and 10.7°±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature between about 159.6° C.and about 169.6° C.; and

3) a thermogravimetric analysis profile showing about 0.5% weight lossbelow about 135° C.

Also provided is an anhydrous crystalline form having:

1) an X-ray powder diffraction pattern comprising peaks, in terms of 2θ,at 8.5°±0.2°, 10.7°±0.2°, and 16.9°±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature between about 160.6° C.and about 168.6° C.; and

3) a thermogravimetric analysis profile showing about 0.25% weight lossbelow about 135° C.

Also provided is an anhydrous crystalline form having:

1) an X-ray powder diffraction pattern comprising peaks, in terms of 2θ,at 8.5°±0.2°, 10.7°±0.2°, 16.9°±0.2°, 25.4°±0.2°, and 11.10±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature between about 162.6° C.and about 166.6° C.; and

3) a thermogravimetric analysis profile showing about 0.05% weight lossbelow about 135° C.

Also provided is an anhydrous crystalline form having:

1) an X-ray powder diffraction pattern comprising peaks, in terms of 2θ,at 8.5°±0.2°, 10.7°±0.2°, 16.9°±0.2°, 25.4°±0.2°, 11.1°±0.2°, 9.8°±0.2°,and 17.4°±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature between about 163.6° C.and about 165.6° C.; and

3) a thermogravimetric analysis profile showing about 0.05% weight lossbelow about 135° C.

Also provided is an anhydrous crystalline form having:

1) an X-ray powder diffraction pattern comprising peaks, in terms of 2θ,at 8.5°±0.2°, 10.7°±0.2°, 16.9°±0.2°, 25.4°±0.2°, 11.1°±0.2°, 9.8°±0.2°,17.4°±0.2°, 22.1°±0.2°, and 16.5°±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature at about 164.6° C.; and

3) a thermogravimetric analysis profile showing about 0.05% weight lossbelow about 135° C.

Also provided is an anhydrous crystalline form having:

1) an X-ray powder diffraction pattern comprising peaks, in terms of 2θ,at 8.5°±0.2°, 10.7°±0.2°, 16.9°±0.2°, 25.4°±0.2°, 11.1°±0.2°, 9.8°±0.2°,17.4°±0.2°, 22.1°±0.2°, 16.5°±0.2°, 14.5°±0.2°, 11.8°±0.2°, and18.9°±0.2°;

2) a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature at about 164.6° C.; and

3) a thermogravimetric analysis profile showing about 0.05% weight lossbelow about 135° C.

Also provided is an anhydrous crystalline form having:

1) an X-ray powder diffraction pattern substantially as shown in FIG.16;

2) a differential scanning calorimetry thermogram substantially as shownin FIG. 17; and

3) a thermogravimetric analysis profile substantially as shown in FIG.17.

In some embodiments, the compound of Formula Ia, or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof is(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide or apharmaceutically acceptable salt, solvate, and/or hydrate thereof andthe one or more known pharmaceutical agent is morphine.

Additionally, chemical genera and individual compounds, for examplethose compounds found in the above list including diastereoisomers andenantiomers thereof, encompass all pharmaceutically acceptable salts,solvates, and particularly hydrates, and N-oxides thereof:

The compounds of the Formula Ia may be prepared according to relevantpublished literature procedures that are used by one skilled in the art.Exemplary reagents and procedures for these reactions appear hereinafterin the working Examples. Protection and deprotection may be carried outby procedures generally known in the art (see, for example, Greene, T.W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3rdEdition, 1999 [Wiley]).

It is understood that the present invention embraces eachdiastereoisomer, each enantiomer and mixtures thereof of each compoundand generic formulae disclosed herein just as if they were eachindividually disclosed with the specific stereochemical designation foreach chiral carbon. Separation of the individual isomers (such as, bychiral HPLC, recrystallization of diastereoisomeric mixtures and thelike) or selective synthesis (such as, by enantiomeric selectivesyntheses and the like) of the individual isomers is accomplished byapplication of various methods which are well known to practitioners inthe art.

The combinations disclosed herein are useful in the treatment of pain,and in the amelioration of symptoms thereof. The analgesic properties ofcannabinoids have been recognized for many years. For example, animalstudies have demonstrated that the CB₁/CB₂ agonists anandamide, THC,CP55,940 and WIN 55212-2 are effective against acute and chronic painfrom chemical, mechanical, and thermal pain stimuli (reviewed in Walkerand Huang (2002) Pharmacol. Ther. 95:127-135; reviewed in Pacher, P etal. (2006) Pharmacol. Rev. 58(3): 389-462). In humans, topicaladministration of the CB₁/CB₂ agonist HU-210 attenuatescapsaicin-induced hyperalgesia and allodynia (Rukwied, R. et al. (2003)Pain 102:283-288), and co-administration of the CB₁/CB₂ agonist THC andcannabidiol (nabiximols, trademark Sativex®) provides relief fromcancer-associated pain (GW Pharmaceuticals press release Jan. 19, 2005,Jun. 19, 2007) and multiple-sclerosis-associated pain and spasticity (GWPharmaceuticals press release Sep. 27, 2005, Mar. 11, 2009).

The role of CB₁ in mediating these analgesic effects is well-documented(reviewed in Manzanares, J. et al. (2006) Current Neuropharmacology4:239-57; reviewed in Pacher, P. et al. (2006) Pharmacol. Rev. 58(3):389-462). For example, blockade of peripheral or central CB₁ leads tohyperalgesia (Richardson, J. D. et al. (1997) Eur. J. Pharmacol.345:145-153; Calignano, A. et al. (1998) Nature 394:277-281), whereasCB₁ activation by exogenous administration of a CB₁ agonistarachidonyl-2-chloroethylamide reduces pain (Furuse, S. et al. (2009)Anesthesiology 111(1):173-86).

Although less well-documented, CB₂ also plays a role in mediatinganalgesic effects of cannabinoids (reviewed in Guindon and Hohmann(2008) Br. J. Pharmacol. 153:319-334). For example, systemic delivery ofthe CB₂-selective agonist AM1241 suppresses hyperalgesia induced in thecarrageenan, capsaicin, and formalin models of inflammatory pain inrodents (reviewed in Guindon and Hohmann (2008) Br. J. Pharmacol.153:319-334). Local (subcutaneous) or systemic administration of AM1241also reverses tactile and thermal hypersensitivity in rats followingligation of spinal nerves in the chronic constriction injury model ofneuropathic pain (Malan, T. P. et al. (2001) Pain 93:239-245; Ibrahim,M. M. et al. (2003) Proc. Natl. Acad. Sci. 100(18):10529-10533), aneffect which is inhibited by treatment with the CB₂-selective antagonistAM630 (Ibrahim, M. M. et al. (2005) Proc. Natl. Acad. Sci.102(8):3093-8). The CB₂-selective agonist GW405833 administeredsystemically significantly reverses hypersensitivity to mechanicalstimuli in rats following ligation of spinal nerves (Hu, B. et al.(2009) Pain 143:206-212). Thus, CB₂-selective agonists have also beendemonstrated to attenuate pain in experimental models of acute,inflammatory, and neuropathic pain, and hyperalgesia.

Accordingly, CB₂-specific agonists and/or CB₁/CB₂ agonists find use inthe treatment and/or prophylaxis of acute nociception and inflammatoryhyperalgesia, as well as the allodynia and hyperalgesia produced byneuropathic pain. For example, these agonists are useful as an analgesicto treat pain arising from autoimmune conditions; allergic reactions;bone and joint pain; muscle pain; dental pain; nephritic syndrome;scleroderma; thyroiditis; migraine and other headache pain; painassociated with diabetic neuropathy; fibromyalgia, HIV-relatedneuropathy, sciatica, and neuralgias; pain arising from cancer; and painthat occurs as an adverse affect of therapeutics for the treatment ofdisease.

Furthermore, although cannabinoids exert their antinociceptive effectsby complex mechanisms involving effects on the central nervous system,spinal cord, and peripheral sensory nerves (reviewed in Pacher, P. etal. (2006) Pharmacol. Rev. 58(3): 389-462), an analysis of models ofinflammatory and neuropathic pain in mice that are deficient for CB₁only in nociceptive neurons localized in the peripheral nervous systemdemonstrates that the contribution of CB₁-type receptors expressed onthe peripheral terminals of nociceptors to cannabinoid-induced analgesiais paramount (Agarwal, N. et al. (2007) Nat. Neurosci. 10(7): 870-879).Accordingly, agonists of CB₁ that are unable to cross the blood brainbarrier still find use in the treatment and/or prophylaxis of acutepain, inflammatory pain, neuropathic pain, and hyperalgesia.

The severity of the pain can be assessed with self-reported measures asis known in the art. Generally, pain is assessed at rest, withappropriate activity (e.g., ambulation, cough), at baseline (prior toadministration of the compound of Formula Ia or a pharmaceuticallyacceptable salt, solvate, hydrate, and/or N-oxide thereof and at regularintervals thereafter. Some of the most commonly used pain assessmentinstruments include the visual analog scale (VAS), numeric rating scale(NRS), and categorical Likert scale. The VAS is a written assessmentthat typically utilizes a unmarked 100-mm line with the left end markedas “no pain” and the right end marked as “worst pain imaginable.”Subjects put a mark on the line corresponding to their level of pain.The NRS can be applied in either written or verbal form and typicallyutilizes a rating from 0 (corresponding to “no pain”) to 10(corresponding to “worst pain imaginable”). Likert scales are typicallyfour- or five-item instruments (e.g., ratings of “none”, “mild”,“moderate”, “severe”) that attempt to quantify pain.

It is understood that when the phrase “pharmaceutically acceptablesalts, solvates and hydrates” is used when referring to a particularformula herein, it is intended to embrace solvates and/or hydrates ofcompounds of the particular formula, pharmaceutically acceptable saltsof compounds of the particular formula as well as solvates and/orhydrates of pharmaceutically acceptable salts of compounds of theparticular formula.

The compounds described herein can be administrated in a wide variety oforal and parenteral dosage forms. It will be apparent to those skilledin the art that the following dosage forms may comprise, as the activecomponent, either a compound described herein or a pharmaceuticallyacceptable salt or as a solvate or hydrate thereof. Moreover, varioushydrates and solvates of the compounds described herein and their saltswill find use as intermediates in the manufacture of pharmaceuticalcompositions. Typical procedures for making and identifying suitablehydrates and solvates, outside those mentioned herein, are well known tothose in the art; see for example, pages 202-209 of K. J. Guillory,“Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids,”in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Brittan, Vol.95, Marcel Dekker, Inc., New York, 1999, incorporated herein byreference in its entirety. Also provided are hydrates and solvates ofcompounds of Formula Ia and/or their pharmaceutical acceptable salts, asdescribed herein, that can be isolated and characterized by methodsknown in the art, such as, thermogravimetric analysis (TGA), TGA-massspectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction(XRPD), Karl Fisher titration, high resolution X-ray diffraction, andthe like. There are several commercial entities that provide quick andefficient services for identifying solvates and hydrates on a routinebasis. Example companies offering these services include WilmingtonPharmaTech (Wilmington, Del.), Avantium Technologies (Amsterdam) andAptuit (Greenwich, Conn.).

Polymorphism is the ability of a substance to exist as two or morecrystalline phases that have different arrangements and/or conformationsof the molecules in the crystal lattice. Polymorphs show the sameproperties in the liquid or gaseous state but they behave differently inthe solid state.

Besides single-component polymorphs, drugs can also exist as salts andother multicomponent crystalline phases. For example, solvates andhydrates may contain an API host and either solvent or water molecules,respectively, as guests. Analogously, when the guest compound is a solidat room temperature, the resulting form is often called a cocrystal.Salts, solvates, hydrates, and cocrystals may show polymorphism as well.Crystalline phases that share the same API host, but differ with respectto their guests, may be referred to as pseudopolymorphs of one another.

Solvates contain molecules of the solvent of crystallization in adefinite crystal lattice. Solvates, in which the solvent ofcrystallization is water, are termed hydrates. Because water is aconstituent of the atmosphere, hydrates of drugs may be formed rathereasily.

By way of example, Stahly recently published a polymorph screens of 245compounds consisting of a “wide variety of structural types” revealedthat about 90% of them exhibited multiple solid forms. Overall,approximately half the compounds were polymorphic, often having one tothree forms. About one-third of the compounds formed hydrates, and aboutone-third formed solvates. Data from cocrystal screens of 64 compoundsshowed that 60% formed cocrystals other than hydrates or solvates. (G.P. Stahly, Crystal Growth & Design (2007), 7(6), 1007-1026.)

As will be recognized, the steps of the methods described herein neednot be performed any particular number of times or in any particularsequence. Additional objects, advantages and novel features of thisinvention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1 Syntheses

Illustrated syntheses for compounds described herein are shown in FIGS.5 through 10 where the symbols have the same definitions as usedthroughout this disclosure.

The compounds and their syntheses are further illustrated by thefollowing examples. The following examples are provided to furtherdefine the invention without, however, limiting the invention to theparticulars of these examples. The compounds described herein, supra andinfra, are named according to AutoNom version 2.2, AutoNom 2000, CSChemDraw Ultra Version 7.0.1, or CS ChemDraw Ultra Version 9.0.7. Incertain instances common names are used and it is understood that thesecommon names would be recognized by those skilled in the art.

Chemistry:

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on aBruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI(Broad Band Inverse) and z-gradient. Chemical shifts are given in partsper million (ppm) with the residual solvent signal used as reference.NMR abbreviations are used as follows: s=singlet, d=doublet, dd=doubletof doublets, ddd=doublet of doublet of doublets, dt=doublet of triplets,t=triplet, td=triplet of doublets, tt=triplet of triplets, q=quartet,m=multiplet, bs=broad singlet, bt=broad triplet. Microwave irradiationswere carried out using a Smith Synthesizer™ or an Emrys Optimizer™(Biotage). Thin-layer chromatography (TLC) was performed on silica gel60 F₂₅₄ (Merck), preparatory thin-layer chromatography (prep TLC) waspreformed on PK6F silica gel 60 Å 1 mm plates (Whatman) and columnchromatography was carried out on a silica gel column using Kieselgel60, 0.063-0.200 mm (Merck). Evaporation was done under reduced pressureon a Büchi rotary evaporator.

LCMS spec: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.

Example 1.1 Preparation of(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (Intermediate 1) Step A: Preparation of(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid Ethyl Ester. Method A

To a solution of (1R,5S)-bicyclo[3.1.0]hexan-2-one (9.19 g, 96 mmol) anddiethyl oxalate (12.98 mL, 96 mmol) in absolute ethanol (300 mL) wasadded a 1.0 M THF solution of potassium tert-butoxide (105 mL, 105mmol). The resulting yellow solution was stirred at 20° C. for 2 h.(2,4-difluorophenyl)hydrazine hydrochloride (17.26 g, 96 mmol) was addedfollowed by a 3.0 M aqueous solution of hydrogen chloride (96 mL, 287mmol). The reaction was stirred at 40° C. for 18 h. The volume wasreduced by about 200 mL, and then brine (300 mL) was added. The mixturewas extracted with dichloromethane (3×250 mL). The combined organicextracts were dried (MgSO₄), filtered, and then concentrated. Theresidue was purified by silica gel flash chromatography to give thetitle compound as a yellow solid (18.4 g). LCMS m/z=305.3 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 0.49 (td, J=4.8, 3.3 Hz, 1H), 1.16 (td, J=7.8,5.0 Hz, 1H), 1.38 (t, J=7.1 Hz, 3H), 2.11-2.16 (m, 1H), 2.24-2.30 (m,1H), 2.90 (d, J=16.6 Hz, 1H), 3.03 (dd, J=16.4, 6.3 Hz, 1H), 4.38 (q,J=7.1 Hz, 2H), 6.97-7.02 (m, 2H), 7.66-7.72 (m, 1H).

Step B: Preparation of(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid. Method B

To a solution of(1aR,5aR)-2-(2,4-difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ethyl ester (17.4 g, 57.2 mmol) in methanol (100 mL) and THF (100mL) was added a 2.0 M aqueous solution of sodium hydroxide (86 mL, 172mmol). The resulting orange solution was stirred at 23° C. for 3 h. Theorganic solvents were removed under reduced pressure. The remainingaqueous solution was diluted to 150 mL with water and then acidified topH 2 by addition of 6 M HCl while stirring vigorously. The precipitatewas collected by filtration, rinsed with water, and then dried underreduced pressure to give the title compound as a tan solid (15.62 g).LCMS m/z=277.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.41 (td, J=4.6,3.4 Hz, 1H), 1.15 (td, J=7.8, 4.7 Hz, 1H), 2.16-2.21 (m, 1H), 2.23-2.29(m, 1H), 2.76 (d, J=16.2 Hz, 1H), 2.90 (dd, J=16.4, 6.2 Hz, 1H),7.27-7.32 (m, 1H), 7.56-7.62 (m, 1H), 7.75 (td, J=9.0, 5.9 Hz, 1H),12.93 (bs, 1H).

Example 1.2 Preparation of(1aR,5aR)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (Intermediate 2) Step A: Preparation of Potassium2-Ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate

To a solution of (1R,5S)-bicyclo[3.1.0]hexan-2-one (10 g, 91 mmol) anddiethyl oxalate (12.29 mL, 91 mmol) in absolute ethanol (250 mL) wasadded a 1.0 M THF solution of potassium tert-butoxide (91 mL, 91 mmol).The resulting yellow solution was stirred at 20° C. for 3 h. The mixturewas diluted with diethyl ether (250 mL). The precipitate was collectedby filtration, rinsed with diethyl ether, and then dried under reducedpressure to give the title compound as a yellow solid (16.7 g). LCMSm/z=197.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.14 (td, J=4.5, 3.4Hz, 1H), 0.78 (td, J=8.0, 3.3 Hz, 1H), 1.15 (t, J=7.2 Hz, 3H), 1.26-1.31(m, 1H), 1.41-1.47 (m, 1H), 2.27 (dd, J=14.2, 1.4 Hz, 1H), 2.39 (dd,J=14.2, 6.2 Hz, 1H), 3.91-4.01 (m, 2H).

Step B: Preparation of(1aR,5aR)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid Ethyl Ester. Method C

To a stirred suspension of2-ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate(300 mg, 1.28 mmol) in ethanol (5 mL) was added 2-hydrazinylpyrazine(141 mg, 1.28 mmol) followed by 6 N HCl (0.5 mL, 3.0 mmol). The reactionwas stirred overnight at room temperature. The reaction was diluted withH₂O and extracted with DCM. The combined organic phases were washed withH₂O, dried over MgSO₄, and concentrated. Purification by silica gelflash chromatography gave the title compound (150 mg). LCMS m/z=271.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.47 (td, J=4.7 and 3.4 Hz, 1H),1.22-1.28 (m, 1H), 1.39 (t, J=7.1 Hz, 3H), 2.26-2.30 (m, 1H), 2.77-2.82(m, 1H), 2.87 (d, J=16.6 Hz, 1H), 2.98 (dd, J=16.6 and 6.3 Hz, 1H), 4.40(q, J=7.1 Hz, 2H), 8.40 (dd, J=2.6 and 1.5 Hz, 1H), 8.51 (d, J=2.5 Hz,1H), 9.39 (d, J=1.3 Hz, 1H).

Step C: Preparation of(1aR,5aR)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid. Method D

To a solution of(1aR,5aR)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ethyl ester (150 mg, 0.56 mmol) in dioxane (2 mL) was added 1 NLiOH (1.1 mL, 1.11 mmol). The reaction was stirred for 1 h at 80° C.,and cooled to room temperature. The reaction was acidified to pH 2 with4 N HCl and diluted with H₂O to form precipitate. The resultingprecipitate was collected by filtration, rinsed with water, and thendried to give the title compound as a white solid (100 mg). LCMSm/z=243.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.43 (td, J=4.5 and3.4 Hz, 1H), 1.26 (td, J=7.7 and 4.4 Hz, 1H), 2.26-2.33 (m, 1H),2.70-2.79 (m, 2H), 2.89 (dd, J=16.6 and 6.3 Hz, 1H), 8.60 (dd, J=2.6 and1.5 Hz, 1H), 8.67 (d, J=2.6 Hz, 1H), 9.17 (d, J=1.4 Hz, 1H), 13.01 (s,1H).

Example 1.3 Preparation of(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1,1-dimethyl-ethyl)-amide (Compound 493)

To a stirred solution of Intermediate 1 (see Example 1.1, 2 g, 7.24mmol), benzotriazole-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate (PyBOP, 4.52 g, 8.69 mmol) and DIEA (2.52 mL, 14.48mmol) in DMF (20 mL) was added 2-amino-2-methylpropan-1-ol (0.833 mL,8.69 mmol). The reaction was stirred at room temperature overnight, thenpoured into water, and extracted with ethyl acetate. The combinedorganics were dried and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a white solid(2.08 g). LCMS m/z=348.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.48 (td,J=4.7, 3.3 Hz, 1H), 1.16 (td, J=7.8, 4.9 Hz, 1H), 1.371 (s, 3H), 1.376(s, 3H), 2.08-2.13 (m, 1H), 2.25-2.31 (m, 1H), 2.94 (d, J=16.8 Hz, 1H),3.04 (dd, J=16.4, 6.2 Hz, 1H), 3.68 (d, J=3.5 Hz, 2H), 4.81-4.84 (m,1H), 6.88 (bs, 1H), 6.99-7.05 (m, 2H), 7.59-7.65 (m, 1H).

Example 1.4 Preparation of(1aR,5aR)-2-(5-Cyano-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1,1-dimethyl-ethyl)-amide (Compound 264)

A heterogeneous mixture of(1aR,5aR)-2-(5-bromo-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-amide (40 mg, 0.10 mmol) andcyanocopper (13.7 mg, 0.15 mmol) in NMP (1.0 mL) in a heavy walled tubewas heated at 200° C. under microwave irradiation for 2 h. The reactionwas filtered and purified by preparative HPLC to give the titlecompound. LCMS m/z=339.6 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.46 (td,J=4.7 and 3.4 Hz, 1H), 1.29 (td, J=8.0 and 4.7 Hz, 1H), 1.42 (s, 3H),1.43 (s, 3H), 2.30-2.37 (m, 1H), 2.71-2.77 (m, 1H), 2.92 (d, J=17.0 Hz,1H), 3.01 (dd, J=16.8 and 6.2 Hz, 1H), 3.71 (s, 2H), 4.29 (s, 1H), 6.90(s, 1H), 8.72 (d, J=1.4 Hz, 1H), 9.33 (d, J=1.4 Hz, 1H).

Example 1.5 Preparation of(1aR,5aR)-2-(5-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1,1-dimethyl-ethyl)-amide (Compound 309)

Step A: Preparation of(1aR,5aR)-2-(5-Fluoropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid Ethyl Ester

To a solution of hydrazine monohydrate (3.13 mL, 64.6 mmol) in 1-butanol(8 mL) in a thick-walled glass tube was added 2-chloro-5-fluoropyridine(1.00 g, 7.60 mmol). The vessel was flushed with nitrogen then sealed.The solution was heated under microwave irradiation at 200° C. for 8 h.The reaction was concentrated under reduced pressure leaving an orangesolid. The solid was taken up in ethyl acetate (30 mL), and theinsoluble material was removed by filtration. The filtrate wasconcentrated to give an orange solid (0.8 g) as a 39:61 mixture of5-fluoro-2-hydrazinylpyridine and 2-chloro-5-hydrazinylpyridine.

The title compound was prepared in a manner similar to that described inMethod C using potassium2-ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolateand mixture of 5-fluoro-2-hydrazinylpyridine and2-chloro-5-hydrazinylpyridine. LCMS m/z=288.2 [M+H]⁺.

Step B: Preparation of(1aR,5aR)-2-(5-Fluoropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid.

The title compound was prepared in a manner similar to that described inMethod B using(1aR,5aR)-2-(5-fluoropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ethyl ester. LCMS m/z=260.2 [M+H]⁺.

Step C: Preparation of(1aR,5aR)-2-(5-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1,1-dimethyl-ethyl)-amide

The title compound was prepared in a manner similar to that described inMethod G using(1aR,5aR)-2-(5-fluoropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid and 2-amino-2-methylpropan-1-ol. LCMS m/z=331.2 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.24 (td, J=7.9, 4.8 Hz,1H), 1.404 (s, 3H), 1.408 (s, 3H), 2.24-2.30 (m, 1H), 2.74-2.79 (m, 1H),2.91 (d, J=16.7 Hz, 1H), 3.00 (dd, J=16.6, 6.2 Hz, 1H), 3.70 (d, J=6.2Hz, 2H), 4.72 (t, J=6.3 Hz, 1H), 6.92 (s, 1H), 7.55 (ddd, J=9.1, 7.6,3.0 Hz, 1H), 7.91 (dd, J=9.1, 3.9 Hz, 1H), 8.31 (d, J=2.8 Hz, 1H).

Example 1.6 Preparation of Phosphoric Acidmono-(2-{[(1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-2-methyl-propyl)Ester (Compound 646)

A solution of(1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-amide (500 mg, 1.482 mmol) inpyridine (10 mL) was cooled in a dry-ice/acetone bath until the mixturesolidified. The cooling bath was removed and phosphoryl trichloride(0.691 mL, 7.41 mmol) was added as soon as the mixture melted (ca −42°C.). The cooling bath was replaced periodically, maintaining thetemperature at −42° C. while stirring for 45 minutes. Still at −42° C.,50 mL 0.5 M aqueous HCl was added. The volume was reduced to 20 mL bydistillation under reduced pressure (50° C. water bath). The remainingsolution was purified by preparative HPLC to give a white solid (338mg). The solid was suspended in water (10 mL) and acetonitrile (2 mL).Sodium carbonate (81.5 mg, 0.769 mmol) was added to form a solution. Theresulting solution was lyophilized to give the sodium salt of the titlecompound as a white solid (385 mg). LCMS m/z=418.3 [M+H]⁺; ¹H NMR (400MHz, D₂O) δ ppm 0.53-0.56 (m, 1H), 1.33-1.38 (m, 1H), 1.53 (s, 6H),2.41-2.47 (m, 1H), 2.69-2.73 (m, 1H), 2.89 (d, J=16.4 Hz, 1H), 3.00 (dd,J=16.4, 6.2 Hz, 1H), 3.91 (d, J=4.2 Hz, 2H), 7.26 (d, J=4.2 Hz, 1H),8.26-7.33 (s, 1H), 8.72 (d, J=4.6 Hz, 1H). ³¹P NMR (162 MHz, D₂O, nodecoupling) δ ppm 3.36 (t, J=4.5 Hz, 1H).

Example 1.7 Preparation of(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide (Compound 696)

Step A: Preparation of(1aS,5aS)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid

The title compound was prepared in a manner similar to that described inExample 1.2. LCMS m/z=243.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.43(td, J=4.6, 3.2 Hz, 1H), 1.26 (td, J=8.0, 4.6 Hz, 1H), 2.27-2.33 (m,1H), 2.71-2.75 (m, 1H), 2.75 (d, J=16.7 Hz, 1H), 2.89 (dd, J=16.4, 6.4Hz, 1H), 8.61 (dd, J=2.5, 1.4 Hz, 1H), 8.67 (d, J=2.7 Hz, 1H), 9.17 (d,J=1.4 Hz, 1H), 12.99 (s, 1H).

Step B: Preparation of(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide

The title compound was prepared in a manner similar to that described inMethod G, using(1aS,5aS)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid and (S)-2-amino-3,3-dimethylbutan-1-ol. LCMS m/z=342.2 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 0.48 (td, J=4.6, 3.4 Hz, 1H), 1.05 (s, 9H),1.24 (td, J=8.0, 4.7 Hz, 1H), 2.26-2.32 (m, 1H), 2.74-2.78 (m, 1H), 2.94(d, J=16.8 Hz, 1H), 3.01 (dd, J=16.7, 6.1 Hz, 1H), 3.67-3.72 (m, 1H),3.93-3.98 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 8.42 (dd, J=1.4, 0.9 Hz, 1H),8.51 (d, J=2.7 Hz, 1H), 9.26 (d, J=1.1 Hz, 1H).

Example 1.8 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide (Compound 699).Method PPP

To a solution of(1aS,5aS)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (900 mg, 2.64 mmol)in chloroform (10 mL) was added 3-chlorobenzoperoxoic acid (1772 mg,7.91 mmol). The reaction was stirred at 23° C. for 3 h. Additional MCPBA(1.2 g) was added and stirring was continued at room temperature for 18h. The mixture was purified by silica gel column chromatography to givethe title compound (550 mg) as a white solid. LCMS m/z=358.3 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 0.49 (td, J=4.6, 3.3 Hz, 1H), 1.03 (s, 9H),1.27 (td, J=8.0, 4.9 Hz, 1H), 2.08 (bs, 1H), 2.27-2.33 (m, 1H),2.71-2.76 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.7, 6.1 Hz,1H), 3.65-3.71 (m, 1H), 3.92-3.97 (m, 2H), 6.97 (d, J=8.5 Hz, 1H), 7.99(dd, J=4.0, 1.4 Hz, 1H), 8.28 (d, J=4.2 Hz, 1H), 8.78 (dd, J=1.4, 0.8Hz, 1H).

A sample was recrystallized from CH₂Cl2/hexane to give a crystallinesolvate. A thermogravimetric analysis (TGA) thermogram for this solvateshowed a loss of ˜5% weight occurring with a melting endotherm at 164°C.

A non-solvated form of Compound 699 was slurried in CH₂Cl₂ and stirredat −28° C. overnight. The suspension was filtered using a centrifugefilter and air dried prior to powder X-ray diffraction pattern (PXRD)analysis. The PXRD pattern showed the material following CH₂Cl₂ slurryto be indistinguishable from the original solvate form resulting fromrecrystallized from CH₂Cl₂/hexane. The differential scanning calorimetry(DSC) thermogram and thermogravimetric analysis (TGA) thermogram for thecrystalline CH₂Cl₂ solvate obtained from recrystallization usingCH₂Cl₂/hexane is shown in FIG. 11; and the PXRD pattern for each of thecrystalline CH₂Cl₂ solvates obtained from two the different methods(i.e., recrystallization using CH₂Cl₂/hexane; and non-solvated Compound699 slurried in CH₂Cl₂) is shown as an overlay in FIG. 12.

Example 1.9 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Pyridin-2-yl-cyclobutyl)-amide (Compound 700)

The title compound was prepared in a manner similar to that described inMethod G, using(1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid and 1-(pyridin-2-yl)cyclobutanamine. LCMS m/z=389.4 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 0.46 (td, J=4.7, 3.4 Hz, 1H), 1.25 (td, J=7.8,4.8 Hz, 1H), 1.97-2.08 (m, 1H), 2.19-2.31 (m, 2H), 2.70-2.78 (m, 3H),2.84-2.92 (m, 3H), 2.98 (dd, J=16.7, 6.2 Hz, 1H), 7.19 (t, J=5.7 Hz,1H), 7.62 (d, J=8.0 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.98 (dd, J=4.2,1.5 Hz, 1H), 8.00-8.04 (m, 1H), 8.28 (d, J=4.2 Hz, 1H), 8.61-8.63 (m,1H), 8.85 (s, 1H).

Example 1.10 Preparation of(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Hydroxymethyl-cyclobutyl)-amide (Compound 698)

The title compound was prepared in a manner similar to that described inExample 1.57. LCMS m/z=342.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.46(dd, J=8.0 and 4.7 Hz, 1H), 1.28 (td, J=7.9 and 5.0 Hz, 1H), 1.87-2.07(m, 2H), 2.22-2.37 (m, 5H), 2.71-2.76 (m, 1H), 2.90 (d, J=17.0 Hz, 1H),2.99 (dd, J=16.7 and 6.2 Hz, 1H), 3.89 (s, 2H), 7.15 (s, NH, 1H), 8.00(dd, J=4.1 and 1.5 Hz, 1H), 8.28 (d, J=4.1 Hz, 1H), 8.80 (s, 1H).

Example 1.11 Preparation of Phosphoric Acidmono-((S)-3,3-Dimethyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl)Ester (Compound 703)

To a solution of phosphoric acidmono-{(S)-3,3-dimethyl-2-[((1aR,5aR)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl)-amino]-butyl}ester(500 mg, 1.074 mmol) in formic acid (5 mL) was added hydrogen peroxide(35% in water, 0.31 mL, 3.22 mmol). The reaction was stirred at 45° C.for 6 h and concentrated. The residue was purified by preparative HPLCto give the title compound (284 mg) as a white solid. LCMS m/z=438.4[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.54 (dd, J=8.0 and 4.7 Hz, 1H),1.05 (s, 9H), 1.25 (td, J=7.9 and 5.0 Hz, 1H), 2.27-2.33 (m, 1H),2.70-2.74 (m, 1H), 2.90 (d, J=17.2 Hz, 1H), 2.99 (dd, J=16.7 and 6.2 Hz,1H), 4.11-4.16 (m, 1H), 4.22-4.34 (m, 2H), 7.55 (d, J=10.2 Hz, NH, 1H),8.02 (dd, J=4.1 and 1.5 Hz, 1H), 8.38 (d, J=4.1 Hz, 1H), 9.32 (s, 1H).

Example 1.12 Preparation of(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1-tetrahydro-pyran-4-yl-ethyl)-amide (Mixture ofCompound 684 and Compound 685)

The title compound was prepared in a manner similar to that described inMethod G using Intermediate 2 and2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol. LCMS m/z=370.2 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 0.46-0.50 (m, 1H), 1.26 (td, J=7.8 and 4.6Hz, 1H), 1.42-1.54 (m, 2H), 1.72 (d, J=12.6 Hz, 2H), 1.98-2.09 (m, 1H),2.27-2.34 (m, 1H), 2.51 (bs, 1H), 2.73-2.79 (m, 1H), 2.94 (d, J=16.8 Hz,1H), 3.01 (dd, J=16.4 and 6.1 Hz, 1H), 3.36-3.45 (m, 2H), 3.82-3.89 (m,3H), 4.01 (dd, J=11.2 and 4.0 Hz, 2H), 7.11 (d, J=7.6 Hz, 1H), 8.42 (dd,J=2.5 and 1.5 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).

Resolution Via Chiral HPLC.

Column: normal phase preparative Chiralcel OD®, 5 cm ID×50 cm L, 20 μmparticle size Eluent: 90% hexane/10% IPA

Gradient: isocratic

Flow: 60 mL/min

Detector: 280 nm

Retention Times: 1^(st) diastereomer—31 min; 2^(nd) diastereomer—35 min.

Example 1.13 Preparation of(1aR,5aR)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (Cyano-dimethyl-methyl)-amide (Compound 625). Method JJJ

A mixture of(1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (cyano-dimethyl-methyl)-amide (0.800 g, 2.071 mmol), lithiumchloride (0.878 g, 20.71 mmol) and tetrabutylammonium bromide (0.334 g,1.036 mmol) in DMA (10 mL) was heated in a heavy-walled sealed tubeunder microwave irradiation at 180° C. for 11 h. The mixture waspurified by preparative HPLC to give the title compound (160 mg) as awhite solid. LCMS m/z=342.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.45(td, J=4.6, 3.4 Hz, 1H), 1.26 (td, J=8.0, 4.9 Hz, 1H), 1.839 (s, 3H),1.844 (s, 3H), 2.25-2.31 (m, 1H), 2.78-2.82 (m, 1H), 2.94 (d, J=16.8 Hz,1H), 3.02 (dd, J=16.7, 6.1 Hz, 1H), 6.91 (s, 1H), 7.23 (dd, J=5.4, 1.9Hz, 1H), 7.92 (d, J=1.8 Hz, 1H) 8.37 (d, J=5.3 Hz, 1H).

Example 1.14 Preparation of(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid [2,2-Dimethyl-1-((S)-methylcarbamoyl)-propyl]-amide (Compound 667)

The title compound was prepared in a manner similar to that described inMethod G using Intermediate 2 and (S)-2-amino-N,3,3-trimethylbutanamide.LCMS m/z=369.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.41 (td, J=4.4and 3.5 Hz, 1H), 0.96 (s, 9H), 1.23-1.28 (m, 1H), 2.25-2.34 (m, 1H),2.60 (d, J=4.5 Hz, 3H), 2.68-2.74 (m, 1H), 2.75 (d, J=16.3 Hz, 1H), 2.90(dd, J=16.2 and 6.4 Hz, 1H), 4.33 (d, J=9.7 Hz, 1H), 7.52 (d, J=9.7 Hz,1H), 8.10-8.15 (m, 1H), 8.60 (dd, J=2.5 and 1.5 Hz, 1H), 8.66 (d, J=2.6Hz, 1H), 9.27 (d, J=1.4 Hz, 1H).

Example 1.15 Preparation of(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide (Compound 642)

The title compound was prepared as described in Method G usingIntermediate 2 and (S)-2-amino-3,3-dimethylbutan-1-ol. LCMS m/z=342.3[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.41 (td, J=4.4 and 3.3 Hz, 1H),0.93 (s, 9H), 1.23-1.28 (m, 1H), 2.25-2.34 (m, 1H), 2.69-2.74 (m, 1H),2.75 (d, J=16.0 Hz, 1H), 2.90 (dd, J=16.2 and 6.4 Hz, 1H), 3.50-3.58 (m,1H), 3.62-3.67 (m, 1H), 3.76-3.82 (m, 1H), 4.52 (t, J=5.0 Hz, 1H), 7.54(d, J=9.8 Hz, 1H), 8.58 (dd, J=2.5 and 1.5 Hz, 1H), 8.64 (d, J=2.6 Hz,1H), 9.39 (d, J=1.4 Hz, 1H).

Example 1.16 Preparation of Phosphoric Acidmono-{(S)-3,3-Dimethyl-2-[((1aR,5aR)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl)-amino]-butyl}Ester(Compound 683)

A mixture of(1aR,5aR)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (600 mg, 1.757mmol) in pyridine (5 mL) was cooled in a dry-ice/acetone bath until itsolidified (pyridine mp=−42° C.). The cooling bath was removed and POCl₃(0.819 ml, 8.79 mmol) was added as soon as the mixture was melted. Themixture was stirred at −42° C. for 2 h and an HCl solution (3.0 M, 15mL) was added. The mixture was filtered and the filtrate was purified byprep-HPLC to give a white solid (260 mg). A solution of the solid (240mg, 0.570 mmol) in H₂O/AcCN (4 mL/3 mL) was mixed with a solution ofNa₂CO₃ (57.3 mg, 0.541 mmol) in H₂O (3 mL). The mixture was dried togive the sodium salt of the title compound (258 mg) as a white solid.LCMS m/z=422.3 [M+H]⁺; ¹H NMR (400 MHz, D₂O) δ ppm 0.42-0.47 (m, 1H),0.99 (s, 9H), 1.21-1.27 (m, 1H), 2.29-2.36 (m, 1H), 2.57-2.62 (m, 1H),2.80 (d, J=16.4 Hz, 1H), 2.92 (dd, J=16.4 and 6.4 Hz, 1H), 3.77-3.83 (m,1H), 3.98-4.08 (m, 2H), 8.48-8.51 (m, 2H), 9.06 (s, 1H).

Example 1.17 Preparation of(1aS,5aS)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (Intermediate 4) Step A: Preparation of(1S,5R)-Bicyclo[3.1.0]hexan-2-one

To a stirred solution of (S)-2-(but-3-enyl)oxirane (100 g, 1019 mmol)and 2,2,6,6-tetramethylpiperidine (86 mL, 509 mmol) in MTBE (1000 mL)cooled in a dry ice/acetone bath, was added dropwise a 2.5 M hexanesolution of BuLi (489 mL, 1223 mmol) at a rate to maintain the internaltemperature at −12 to −5° C. (time of addition=1 h). After addition wascomplete, the reaction was stirred one hour at −5 to 0° C. and quenchedwith 3 M aqueous HCl (545 mL) dropwise (internal temperature rose to 3°C.). The layers were separated and the organic layer was washed with 3 MHCl (200 mL). The combined aqueous layers were extracted with MTBE(2×500 mL). The combined organic layers were washed with brine (3×300mL) and concentrated to give a pale yellow solution (ca. 1000 mL). Tothis solution in a 5 L 3-neck round bottom flask equipped with anoverhead stirrer was added an aqueous solution of dibasic potassiumphosphate (216 g, 1240 mmol), monobasic potassium phosphate (12.8 g, 94mmol), and potassium bromide (18.19 g, 153 mmol) in water (407 mL). Themixture was cooled to −20° C. in a dry-ice/isopropanol bath. TEMPO (4.30g, 27.5 mmol) was added. The temperature was allowed to warm to 0° C.and aqueous sodium hypochlorite (1.54 M, 1059 mL, 1630 mmol) was addeddropwise over 70 min while maintaining the internal temperature between−10 and 0° C. Stirring was continued at 0° C. for another hour. Sodiumsulfite (50 g) was added to quench excess sodium hypochlorite(temperature rose to 12° C.). The layers were separated and the aqueouslayer was extracted twice more with MTBE (500 mL then 250 mL). Thecombined organic layers (total volume ca. 1600 mL) were dried (MgSO₄)then filtered. The solution was concentrated (ca. 300 mL). The residuewas distilled (2 torr/36° C., note: receiving flask was cooled in dryice/acetone bath) to give the title compound (65.8 g) as a light orangeoil. ¹H NMR (400 MHz, CDCl₃) δ 0.93 (td, J=4.6, 3.3 Hz, 1H), 1.20 (td,J=8.0, 4.8 Hz, 1H), 1.74-1.79 (m, 1H), 1.98-2.19 (m, 5H).

Step B: Preparation of 2-Hydrazinylpyrazine

Under nitrogen atmosphere, 2-chloropyrazine (96 mL, 1073 mmol) was addeddropwise to 35 wt % aqueous hydrazine (544 mL, 6009 mmol) at 65° C. over1 h. After the addition, stirring was continued at 63-67° C. for 16 hand the reaction mixture was let stand at room temperature for two days.The mixture was filtered to remove a small amount of precipitate, thenextracted with 10% iPrOH/dichloromethane (5×250 mL). The combinedorganic extracts were dried (MgSO₄), filtered, then concentrated underreduced pressure. The resulting solid was triturated with isopropylacetate (600 mL). The solid was collected by filtration, rinsed withisopropyl acetate, then dried in vacuo to give the title compound (60 g)as a pale yellow solid. LCMS m/z=111.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆)δ 4.21 (s, 2H), 7.70 (d, J=2.8 Hz, 1H), 7.89 (s, 1H), 7.93 (dd, J=2.8,1.5 Hz, 1H), 8.10 (d, J=1.5 Hz, 1H).

Step C: Preparation of(1aS,5aS)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid Ethyl Ester. Method KKK

To a solution of (1S,5R)-bicyclo[3.1.0]hexan-2-one (52.9 g, 539 mmol)and diethyl oxalate (0.073 L, 539 mmol) in absolute ethanol (0.9 L) (notdenatured with methanol) was added a THF solution of potassiumtert-butoxide (1.0 M, 0.539 L, 539 mmol) over 15 min (maintaining thetemperature below 43° C.). The resulting yellow solution was stirred at40° C. for 3.5 h. 2-Hydrazinylpyrazine (59.4 g, 539 mmol) was addedfollowed by a 6.0 M aqueous solution of hydrogen chloride (0.270 L, 1618mmol). The reaction was stirred at 50° C. for 1.5 h. The mixture waspoured into ice-water (5 L). A precipitate appeared immediately. Aftersitting for 30 minutes in an ice bath, the solid was collected byfiltration, rinsed with water (5×1 L), and dried to give the titlecompound (106 g) as an off-white solid ¹H NMR. LCMS m/z=271.2 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ 0.47 (td, J=4.7, 3.3 Hz, 1H), 1.27 (td, J=8.0,4.9 Hz, 1H), 1.41 (t, J=7.1 Hz, 3H), 2.26-2.32 (m, 1H), 2.77-2.82 (m,1H), 2.88 (dd, J=16.7, 1.4 Hz, 1H), 2.99 (dd, J=16.6, 6.4 Hz, 1H), 4.40(q, J=7.1 Hz, 2H), 8.41 (dd, J=2.5, 1.5 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H),9.40 (d, J=1.5 Hz, 1H).

Step D: Preparation of(1aS,5aS)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (Intermediate 4). Method LLL

To a suspension of(1aS,5aS)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ethyl ester (106 g, 392 mmol) in MeOH (300 mL) and THF (300 mL) wasadded a 2.0 M aqueous solution of NaOH (235 mL, 471 mmol). The reactionwas stirred at 23° C. for 20 h. The organic solvents were removed onrotovap. The remaining aqueous solution was diluted to ˜1.5 L with H₂Othen acidified to pH ˜2 with 6 M HCl (ca. 95 mL). The resulting fineprecipitate was collected by filtration, rinsed with water, and dried togive the title compound (95 g) as a white solid. LCMS m/z=243.1 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 0.43 (td, J=4.6, 3.2 Hz, 1H), 1.26 (td,J=8.0, 4.4 Hz, 1H), 2.27-2.33 (m, 1H), 2.71-2.75 (m, 1H), 2.76 (d,J=16.8 Hz, 1H), 2.89 (dd, J=16.4, 6.4 Hz, 1H), 8.61 (dd, J=2.7, 1.5 Hz,1H), 8.67 (d, J=2.5 Hz, 1H), 9.17 (d, J=1.5 Hz, 1H), 13.02 (s, 1H).

Example 1.18 Preparation of(1aS,5aS)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid N-Oxide (Intermediate 5)

To a suspension of(1aS,5aS)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (68.8 g, 284 mmol) in formic acid (688 mL) at room temperature wasadded a 50 wt % aqueous solution of hydrogen peroxide (82 mL, 1420mmol). The mixture was heated to 64° C. The reaction was stirred at 58to 64° C. for 3 h. Another 8 mL 50% H₂O₂ was added and stirringcontinued another hour at 60° C. The mixture was cooled to roomtemperature and diluted with water (1 L). After cooling in an ice-bathfor 1 h, the precipitate was collected by filtration, rinsed with water,and dried in vacuo to give a pale yellow solid (56.7 g) which containsabout 2% starting material. The material was re-subjected to reactionconditions aforementioned to give the title compound (45 g). LCMSm/z=259.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 0.42 (td, J=4.4, 3.3 Hz,1H), 1.27 (td, J=7.8, 4.7 Hz, 1H), 2.27-2.33 (m, 1H), 2.68-2.73 (m, 1H),2.75 (dd, J=16.9, 1.5 Hz, 1H), 2.88 (dd, J=16.4, 6.4 Hz, 1H), 8.33 (dd,J=4.2, 1.5 Hz, 1H), 8.50 (dd, J=4.2, 0.6 Hz, 1H), 8.54 (dd, J=1.5, 0.6Hz, 1H), 13.08 (s, 1H).

Example 1.19 Preparation of(1aR,5aR)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid

The title compound was prepared in a manner similar to that described inExample 1.17 using (R)-2-(but-3-enyl)oxirane. LCMS m/z=243.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) 0.43 (td, J=4.5 and 3.4 Hz, 1H), 1.26 (td, J=7.7and 4.4 Hz, 1H), 2.26-2.33 (m, 1H), 2.70-2.79 (m, 2H), 2.89 (dd, J=16.6and 6.3 Hz, 1H), 8.60 (dd, J=2.6 and 1.5 Hz, 1H), 8.67 (d, J=2.6 Hz,1H), 9.17 (d, J=1.4 Hz, 1H), 13.01 (s, 1H).

Example 1.20 Preparation of(1aR,5aR)-2-(Pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid N-Oxide (Intermediate 6)

The title compound was prepared in a manner similar to that described inExample 1.18 using Intermediate 2. LCMS m/z=259.3 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) 0.43 (td, J=4.6 and 3.3 Hz, 1H), 1.28 (td, J=7.9 and 4.8Hz, 1H), 2.27-2.33 (m, 1H), 2.68-2.73 (m, 1H), 2.75 (d, J=16.7 Hz, 1H),2.88 (dd, J=16.5 and 6.4 Hz, 1H), 8.33 (dd, J=4.2 and 1.5 Hz, 1H), 8.50(d, J=4.2 Hz, 1H), 8.55 (d, J=1.0 Hz, 1H), 13.10 (bs, 1H).

Example 1.21 Preparation of(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Methyl-cyclobutyl)-amide (Compound 821). Method UU

A solution of Intermediate 6 (200 mg, 0.77 mmol), HATU (300 mg, 0.78mmol), and Et₃N (0.15 mL, 1.17 mmol) in acetonitrile (5 mL) was stirredfor 10 min at room temperature. 1-Methylcyclobutanamine (70 mg, 0.82mmol) was added into the solution, and the mixture was stirred for 2 hat room temperature. The reaction was diluted with DCM, washed with H₂Oand 1 N HCl, dried with anhydrous MgSO₄, and concentrated. The residuewas purified by column chromatography to give the title compound (120mg). LCMS m/z=326.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.44-0.48 (m, 1H),1.26 (td, J=7.8, 4.8 Hz, 1H), 1.56 (s, 3H), 1.83-1.97 (m, 2H), 2.06-2.14(m, 2H), 2.26-2.33 (m, 1H), 2.41-2.50 (m, 2H), 2.69-2.74 (m, 1H), 2.92(d, J=16.6 Hz, 1H), 3.00 (dd, J=16.6, 6.0 Hz, 1H), 6.87 (s, 1H), 7.97(dd, J=4.0, 1.4 Hz, 1H), 8.28 (d, J=4.2 Hz, 1H), 8.78 (s, 1H).

Example 1.22 Preparation of(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Fluoro-1,1-dimethyl-ethyl)-amide (Compound 897). Method MMM

Step A: Preparation of(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid Ethyl Ester

The title compound was prepared in a manner similar to that described inExample 1.18, Step C, using (1S,5R)-bicyclo[3.1.0]hexan-2-one and4-chloro-2-hydrazinylpyridine. LCMS m/z=348.0 [M+H]⁺.

Step B: Preparation of(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid

To a solution of(1aS,5aS)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ethyl ester (2.1 g, 6.0 mmol) in acetonitrile (30 mL) was addedconcentrated HCl (1.4 mL, 18.0 mmol). The reaction was stirred for 6 hat 80° C. The reaction was cooled down and diluted with H₂O. The solidprecipitate was filtered, washed with H₂O, and dried to give a solid(1.7 g). The solid aforementioned was dissolved in dioxane (10 mL).After addition of 1 N LiOH (9.0 mL), the reaction was stirred at 40° C.for 4 h. The reaction was cooled down to room temperature, diluted withH₂O, and acidified with 4 N HCl to form a precipitate. The solid wasfiltered, washed with H₂O, and dried to give the title compound.

LCMS m/z=276.1 [M+H]⁺.

Step C: Preparation of(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Fluoro-1,1-dimethyl-ethyl)-amide (Compound 897)

The title compound was prepared in a manner similar to that described inMethod UU using(1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid and 1-fluoro-2-methylpropan-2-amine hydrochloride. LCMS m/z=349.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.42-0.47 (m, 1H), 1.24 (td, J=7.9,4.8 Hz, 1H), 1.48 (s, 3H), 1.49 (s, 3H), 2.22-2.29 (m, 1H), 2.76-2.82(m, 1H), 2.90 (d, J=16.8 Hz, 1H), 2.99 (dd, J=16.6, 6.2 Hz, 1H), 4.56(d, J=47 Hz, 2H), 6.80 (s, 1H), 7.20 (dd, J=5.4, 1.9 Hz, 1H), 7.93 (d,J=1.8 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H).

Example 1.23 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2,2,2-Trifluoro-1,1-dimethyl-ethyl)-amide (Compound 919)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 5 and1,1,1-trifluoro-2-methylpropan-2-amine. LCMS m/z=368.3 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 0.44-0.49 (m, 1H), 1.27 (td, J=8.0, 4.8 Hz, 1H), 1.70(s, 6H), 2.27-2.34 (m, 1H), 2.71-2.76 (m, 1H), 2.91 (d, J=17.0 Hz, 1H),3.00 (dd, J=16.7, 6.4 Hz, 1H), 6.81 (s, 1H), 7.99 (dd, J=4.2, 1.6 Hz,1H), 8.28 (dd, J=4.2, 0.6 Hz, 1H), 8.77 (dd, J=1.5, 0.7 Hz, 1H).

Example 1.24 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((1S,2S)-2-Hydroxy-indan-1-yl)-amide (Compound 920)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 5 and(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol. LCMS m/z=390.4 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 0.48-0.52 (m, 1H), 1.30 (td, J=7.9, 5.0 Hz, 1H),2.30-2.37 (m, 1H), 2.73-2.79 (m, 1H), 2.96 (d, J=16.9 Hz, 1H), 2.99-3.03(m, 1H), 3.05 (dd, J=16.7, 6.2 Hz, 1H), 3.37 (dd, J=15.7, 7.7 Hz, 1H),4.46 (s, 1H), 4.55 (q, J=7.7 Hz, 1H), 5.26 (t, J=5.8 Hz, 1H), 7.26-7.34(m, 5H), 7.95 (dd, J=4.0, 1.6 Hz, 1H), 8.28 (dd, J=4.2, 0.6 Hz, 1H),8.75 (dd, J=1.5, 0.7 Hz, 1H).

Example 1.25 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((1S,2R)-2-Hydroxy-indan-1-yl)-amide (Compound 921)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 5 and(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol. LCMS m/z=390.3 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 0.46-0.51 (m, 1H), 1.28 (td, J=8.0, 5.1 Hz, 1H),2.27-2.33 (m, 1H), 2.67-2.73 (m, 1H), 2.96 (d, J=16.8 Hz, 1H), 3.00-3.07(m, 2H), 3.24 (dd, J=16.5, 5.4 Hz, 1H), 4.76 (td, J=5.2, 2.2 Hz, 1H),5.55 (dd, J=8.4, 5.2 Hz, 1H), 7.20-7.34 (m, 4H), 7.56 (d, J=8.4 Hz, 1H),7.79 (dd, J=4.2, 1.6 Hz, 1H), 8.19 (dd, J=4.0, 0.6 Hz, 1H), 8.84 (dd,J=1.4, 0.6 Hz, 1H).

Example 1.26 Preparation of(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid [2-Hydroxy-1-(tetrahydro-pyran-4-yl)-ethyl]-amide (Compound 841)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 6 and2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol. The crude reaction mixturewas purified by preparative HPLC to give a white solid. LCMS m/z=386.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.47 (td, J=4.6 and 3.2 Hz, 1H),1.23-1.29 (m, 1H), 1.40-1.54 (m, 2H), 1.65-1.75 (m, 2H), 1.95-2.05 (m,1H), 2.27-2.33 (m, 1H), 2.30-2.40 (m, 1H), 2.70-2.75 (m, 1H), 2.89-3.04(m, 2H), 3.36-3.45 (m, 2H), 3.82-3.91 (m, 3H), 4.00 (dd, J=11.3 and 3.8Hz, 2H), 7.05 (d, J=8.3 Hz, 1H), 7.99 (d, J=4.1 and 0.9 Hz, 1H), 8.28(d, J=4.1 Hz, 1H), 8.80 (d, J=0.5 Hz, 1H).

Resolution Via Chiral HPLC

Column: Chiralcel OD preparative column, 5 cm ID×50 cm L

Injection: ˜60 mg

Eluent: 50% IPA/Hexanes

Gradient: isocratic

Flow: 60 mL/min

Detector: 280 nm

Retention Time: 1^(st) diastereomer—37.0 min, 2^(nd) diastereomer—44.2min

Example 1.27 Preparation of(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2,2,2-Trifluoro-1,1-dimethyl-ethyl)-amide (Compound 927)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 4 and1,1,1-trifluoro-2-methylpropan-2-amine. LCMS m/z=352.4 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 0.47 (td, J=4.6 and 3.2 Hz, 1H), 1.23-1.29 (m, 1H),1.71 (s, 6H), 2.27-2.33 (m, 1H), 2.74-2.80 (m, 1H), 2.93 (d, J=17.1 Hz,1H), 3.00 (dd, J=16.6 and 6.2 Hz, 1H), 6.94 (s, 1H), 8.42 (dd, J=2.5 and1.5 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 9.25 (d, J=1.4 Hz, 1H).

Example 1.28 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Trifluoromethyl-cyclobutyl)-amide (Compound 765)

Step A: Preparation of 1-(Trifluoromethyl)cyclobutanamine Hydrochloride

1-(Trifluoromethyl)cyclobutanecarboxylic acid (1 g, 5.95 mmol) andtriethylamine (0.912 mL, 6.54 mmol) in anhydrous tert-butanol (20 mL)was stirred at room temperature in the presence of 4 Å molecular sievespowder. To the mixture was added diphenyl phosphorazidate (1.801 g, 6.54mmol). The reaction mixture was refluxed under N₂ for 2 days, filtered,then concentrated in vacuo. The oily residue was stirred in ether, etherlayer was isolated. The procedure was repeated three times. The combinedorganics were washed with 5% citric acid, saturated aqueous NaHCO₃twice, brine, dried over anhydrous Na₂SO₄, and concentrated to givetert-butyl 1-(trifluoromethyl)cyclobutylcarbamate (713 mg) as a whitesolid. The solid was dissolved in 1.25 N HCl in methanol solution (10mL), stirred at 50° C. overnight, and concentrated to give the titlecompound (493 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 1.87-1.97 (m, 1H),2.04-2.15 (m, 1H), 2.44-2.50 (m, 4H), 9.40 (br, 3H).

Step B: Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Trifluoromethyl-cyclobutyl)-amide (Compound 765)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 5 and 1-(trifluoromethyl)cyclobutanaminehydrochloride. LCMS m/z=380.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.47(td, J=4.6, 3.2 Hz, 1H), 1.23-1.29 (m, 1H), 2.04-2.14 (m, 2H), 2.27-2.33(m, 1H), 2.62-2.69 (m, 4H), 2.71-2.76 (m, 1H), 2.92 (d, J=17.1 Hz, 1H),3.00 (dd, J=16.8 and 6.2 Hz, 1H), 6.92 (s, 1H), 7.99 (dd, J=4.1 and 1.5Hz, 1H), 8.29 (dd, J=4.1 and 0.6 Hz, 1H), 8.81 (dd, J=1.5 and 0.6 Hz,1H).

Example 1.29 Preparation of(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Trifluoromethyl-cyclobutyl)-amide (Compound 926)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 4 and 1-(trifluoromethyl)cyclobutanaminehydrochloride. LCMS m/z=364.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.47(td, J=4.6, 3.2 Hz, 1H), 1.23-1.29 (m, 1H), 2.04-2.14 (m, 2H), 2.27-2.33(m, 1H), 2.64-2.70 (m, 4H), 2.74-2.80 (m, 1H), 2.93 (d, J=16.9 Hz, 1H),3.02 (dd, J=16.6 and 6.2 Hz, 1H), 6.99 (s, 1H), 8.42 (dd, J=2.5 and 1.5Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).

Example 1.30 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Trifluoromethyl-cyclopropyl)-amide (Compound 764)

Step A: Preparation of 1-(Trifluoromethyl)cyclopropanamine Hydrochloride

The title compound was prepared in a manner similar to that described inExample 1.28, Step A, using 1-(trifluoromethyl)cyclopropanecarboxylicacid.

Step B: Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Trifluoromethyl-cyclopropyl)-amide (Compound 764)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 5 and 1-(trifluoromethyl)cyclopropanaminehydrochloride. LCMS m/z=366.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.47(td, J=4.6, 3.2 Hz, 1H), 1.23-1.29 (m, 3H), 1.39-1.43 (m, 2H), 2.27-2.33(m, 1H), 2.70-2.75 (m, 1H), 2.92 (d, J=17.0 Hz, 1H), 3.00 (dd, J=16.8and 6.2 Hz, 1H), 7.28 (s, 1H), 8.00 (dd, J=4.1 and 1.5 Hz, 1H), 8.29(dd, J=4.1 and 0.6 Hz, 1H), 8.81 (dd, J=1.5 and 0.6 Hz, 1H).

Example 1.31 Preparation of(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Trifluoromethyl-cyclopropyl)-amide (Compound 930)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 4 and 1-(trifluoromethyl)cyclopropanaminehydrochloride. LCMS m/z=350.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.47(td, J=4.6, 3.2 Hz, 1H), 1.23-1.29 (m, 3H), 1.39-1.43 (m, 2H), 2.27-2.33(m, 1H), 2.74-2.80 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.02 (dd, J=16.7and 6.2 Hz, 1H), 7.31 (s, 1H), 8.42 (dd, J=2.5 and 1.5 Hz, 1H), 8.52 (d,J=2.5 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).

Example 1.32 Preparation of (1aR,5aR)-Pentanedioic Acidmono-((S)-3-Methyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl)Ester (Compound 844) and its Sodium Salt

To a solution of(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2-methyl-propyl)-amide (Compound 690) (100 mg,0.291 mmol), DMAP (17.79 mg, 0.146 mmol) and triethylamine (79 μL, 0.582mmol) in DCM (5 mL) was added dihydro-2H-pyran-2,6(3H)-dione (100 mg,0.874 mmol). The reaction mixture was stirred at room temperatureovernight, then concentrated. The residue was purified by preparativeHPLC. The combined fractions were extracted with DCM. The organic layerswere washed with water twice, dried over anhydrous Na₂SO₄, andconcentrated to give the title compound as a white solid (95 mg). LCMSm/z=458.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 0.42 (td, J=4.6, 3.2 Hz,1H), 0.91 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H), 1.23-1.27 (m, 1H),1.65-1.72 (m, 2H), 1.85-1.92 (m, 1H), 2.18 (t, J=7.5 Hz, 2H), 2.30 (t,J=7.4 Hz, 2H), 2.27-2.33 (m, 1H), 2.65-2.70 (m, 1H), 2.75 (d, J=16.8 Hz,1H), 2.86 (dd, J=16.5 and 6.4 Hz, 1H), 3.92-4.02 (m, 1H), 4.08 (dd,J=11.0 and 8.2 Hz, 1H), 4.25 (dd, J=11.0 and 4.2 Hz, 1H), 8.05 (d, J=9.2Hz, 1H), 8.29 (dd, J=4.1 and 1.5 Hz, 1H), 8.47 (d, J=4.1 Hz, 1H), 8.81(d, J=1.3, 1H), 12.0 (br, 1H).

(1aR,5aR)-Pentanedioic acidmono-((S)-3-methyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl)ester (165 mg, 0.36 mmol) was dissolved in THF (5 mL), heated at 40° C.for 5 min, 0.1 N NaOH solution (3.6 mL, 0.36 mmol) was added slowly,stirred for 30 min while cooled down, then concentrated. The residue waslyophilized to give the sodium salt as white solid (165 mg). LCMSm/z=458.2 [M+H-Na]⁺; ¹H NMR (400 MHz, d₆-DMSO) δ 0.42 (td, J=4.6, 3.2Hz, 1H), 0.91 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H), 1.23-1.27 (m,1H), 1.55-1.62 (m, 2H), 1.80 (t, J=7.0 Hz, 2H), 1.85-1.92 (m, 1H), 2.24(t, J=7.4 Hz, 2H), 2.25-2.33 (m, 1H), 2.65-2.70 (m, 1H), 2.75 (d, J=16.7Hz, 1H), 2.86 (dd, J=16.5 and 6.5 Hz, 1H), 3.91-3.99 (m, 1H), 4.05 (dd,J=11.0 and 7.6 Hz, 1H), 4.22 (dd, J=11.0 and 4.3 Hz, 1H), 8.15 (d, J=9.1Hz, 1H), 8.28 (dd, J=4.2 and 1.5 Hz, 1H), 8.47 (d, J=4.1 Hz, 1H), 9.06(d, J=1.6, 1H).

Example 1.33 Preparation of(1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (Compound 820)

Step A: Preparation of 4-Bromo-2-hydrazinylpyridine

To a solution of 4-bromo-2-fluoropyridine (23.75 g, 135 mmol) in ethanol(120 mL) was added hydrazine monohydrate (65.5 mL, 1350 mmol). Themixture was stirred at 45° C. for 16 h then concentrated. The resultingsolid was triturated with water, collected by filtration, rinsed withwater, and dried under vacuum, to give the title compound (23.2 g) as awhite solid. LCMS m/z=188.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 4.19 (s,2H), 6.69 (dd, J=5.3, 1.8 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 7.69 (s, 1H),7.84 (d, J=5.3 Hz, 1H).

Step B: Preparation of(1aR,5aR)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid Ethyl Ester

The title compound was prepared as described in Method KKK, using(1R,5S)-bicyclo[3.1.0]hexan-2-one and 4-bromo-2-hydrazinylpyridine. LCMSm/z=348.2 [M+H]⁺.

Step C: Preparation of(1aR,5aR)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid

To a solution of(1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ethyl ester (9.0 g, 25.8 mmol) in THF (50 mL) and MeOH (50.0 mL)was added a 2.0 M aqueous solution of sodium hydroxide (25.8 mL, 51.7mmol). The reaction was stirred at 23° C. for 2 h then concentrated toremove the organic solvents. The remaining residue was diluted to 150 mLwith water. This solution was filtered to remove trace insolubleimpurities then acidified to pH ˜3 with 6 M HCl. The resultingprecipitate was collected by filtration, rinsed with water, then driedunder vacuum to give the title compound (8.3 g) as a white solid. LCMSm/z=320.0 [M+H]⁺.

Step D: Preparation of(1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid

(1aR,5aR)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1.00 g, 3.12 mmol) was dissolved in DMA (10 mL). 60 wt % sodiumhydride (0.125 g, 3.12 mmol) was added and the mixture was stirredvigorously for 5 min. Nitrogen was bubbled through the mixture for 10min. Zinc(II) cyanide (0.734 g, 6.25 mmol) and palladiumtetrakistriphenylphosphine (0.180 g, 0.156 mmol) were added. Thereaction was microwaved at 120° C. for 1 h. The reaction was dilutedwith ethyl acetate (20 mL) and methanol (5 mL), filtered, thenconcentrated. The residue was purified by HPLC to give the titlecompound (0.557 g) as a white solid. LCMS m/z=267.2 [M+H]⁺.

Step E: Preparation of(1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (Compound 820)

To a solution of(1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (100 mg, 0.376 mmol), 2-amino-2-methylpropane-1,3-diol (39.5 mg,0.376 mmol), and triethylamine (0.105 mL, 0.751 mmol) in DMF (2 mL) wasadded HATU (157 mg, 0.413 mmol). The reaction was stirred at 23° C., for30 min then concentrated. The residue was purified by silica gel flashcolumn chromatography to give the title compound (125 mg) as a whitesolid. LCMS m/z=354.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.46 (td, J=4.7,3.3 Hz, 1H), 1.27 (td, J=8.0, 4.9 Hz, 1H), 1.36 (s, 3H), 2.27-2.33 (m,1H), 2.78-2.89 (m, 2H), 3.00 (dd, J=16.8, 6.4 Hz, 1H), 3.72-3.77 (m,4H), 3.87-3.94 (m, 2H), 7.23 (m, 1H), 7.42 (dd, J=5.1, 1.0 Hz, 1H),8.16-8.17 (m, 1H), 8.62 (d, J=5.1 Hz, 1H).

Example 1.34 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid N′-tert-Butyl-hydrazide (Compound 902). Method TT

To a solution of Intermediate 5 (129 mg, 0.5 mmol) and HATU (190 mg,0.500 mmol) in DMF (4 mL) was added triethylamine (126 mg, 1.250 mmol)followed by tert-butylhydrazine (44.1 mg, 0.500 mmol) at roomtemperature. The reaction was stirred for 16 h. The reaction mixture wasdiluted with water (100 mL) and extracted with EtOAc (70 mL). Theorganic layer was concentrated and the residue was purified by silicagel column chromatography to give the title compound (87 mg) as a whitesolid. LCMS m/z=329.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.49 (dd, J=8.0and 4.7 Hz, 1H), 1.17 (s, 9H), 1.25-1.31 (m, 1H), 2.29-2.33 (m, 1H),2.72-2.77 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.01 (dd, J=17.0 and 6.2 Hz,1H), 8.00 (dd, J=4.1 and 1.4 Hz, 1H), 8.29 (d, J=4.1 Hz, 1H), 8.80 (d,J=1.4 Hz, 1H).

Example 1.35 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Hydroxymethyl-2-methyl-propyl)-amide (Compound 896)

The title compound was prepared in a manner similar to that described inMethod TT. LCMS m/z=344.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.48 (dd,J=8.0 and 4.7 Hz, 1H), 1.02 (t, J=7.1 Hz, 6H), 1.28 (td, J=8.0 and 5.0Hz, 1H), 1.98-2.04 (m, 1H), 2.28-2.32 (m, 1H), 2.71-2.75 (m, 1H), 2.93(d, J=16.8 Hz, 1H), 3.00 (dd, J=16.7 and 6.3 Hz, 1H), 3.74-3.88 (m, 3H),6.97 (d, J=8.1 Hz, NH, 1H), 7.99 (dd, J=4.1 and 1.5 Hz, 1H), 8.28 (d,J=4.1 Hz, 1H), 8.79 (d, J=1.5 Hz, 1H).

Example 1.36 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-2,2-Dimethyl-1-pyridin-2-yl-propyl)-amide (Compound 767).Method AAA

Step A: Preparation of(R)—N—((S)-2,2-Dimethyl-1-(pyridin-2-yl)propyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamideand(R)—N—((R)-2,2-Dimethyl-1-(pyridin-2-yl)propyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide

To an ice-cooled solution of racemic2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine (1.0 g, 6.09 mmol) andtriethylamine (0.849 mL, 6.09 mmol) in dichloromethane (20 mL) was addeda dichloromethane (5 mL) solution of(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (1.148 mL, 6.09mmol). The solution was stirred at 23° C. for 30 min then loaded onto asilica column. Purification by silica gel flash column chromatographygave the title compound as diastereomers: First-eluting diastereomer(0.56 g) and second-eluting diastereomer (0.504 g) as yellow oils.

First-eluting diastereomer: LCMS m/z=381.4 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ 0.83 (s, 9H), 3.40 (q, J=1.7 Hz, 3H), 4.93 (d, J=9.5 Hz, 1H),7.16-7.20 (m, 2H), 7.38-7.42 (m, 3H), 7.61 (td, J=7.7, 1.8 Hz, 1H),7.65-7.68 (m, 2H), 7.96 (d, J=9.5 Hz, 1H), 8.55 (dt, J=4.5, 1.3 Hz, 1H).

Second-eluting diastereomer: LCMS m/z=381.4 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ 0.96 (s, 9H), 3.44 (q, J=1.4 Hz, 3H), 4.90 (d, J=9.5 Hz, 1H),7.14-7.17 (m, 2H), 7.23-7.31 (m, 3H), 7.41 (d, J=7.3 Hz, 2H), 7.59 (td,J=7.7, 1.8 Hz, 1H), 8.16 (d, J=9.4 Hz, 1H), 8.50 (dt, J=5.3, 1.8 Hz,1H).

Step B: Preparation of (S)-2,2-Dimethyl-1-(pyridin-2-yl)propan-1-amineand (R)-2,2-Dimethyl-1-(pyridin-2-yl)propan-1-amine

Solutions of(R)—N—((S)-2,2-dimethyl-1-(pyridin-2-yl)propyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide(0.56 g, 1.472 mmol) or(R)—N—((R)-2,2-dimethyl-1-(pyridin-2-yl)propyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide(0.56 g, 1.472 mmol) in 48 wt % aqueous hydrogen bromide (5.02 mL, 44.2mmol) were heated under microwave irradiation at 160° C. for 2 h. Themixtures were diluted with water (25 mL), extracted with dichloromethane(3×25 mL), and the dichloromethane extracts discarded. The aqueoussolutions were basified with 2 M aqueous NaOH (25 mL) then extractedwith dichloromethane (3×25 mL). These extracts were dried (MgSO₄),filtered, then concentrated to give enantiomeric2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine derived from first-elutingdiastereomer (0.175 g) and enantiomeric2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine derived from second-elutingdiastereomer (0.200 g) as yellow oils.

Enantiomer derived from first-eluting Mosher amide: LCMS m/z=165.3[M+H]⁺;

Enantiomer derived from second-eluting Mosher amide: LCMS m/z=165.3[M+H]⁺.

Step C: Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-2,2-Dimethyl-1-pyridin-2-yl-propyl)-amide

To a solution of Intermediate 5 (200 mg, 0.774 mmol),(S)-2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine (127 mg, 0.774 mmol),and triethylamine (0.216 mL, 1.549 mmol) in DMF (3 mL) was added HATU(324 mg, 0.852 mmol). The reaction was stirred at 23° C. for 1 h thendiluted with DMSO (2 mL). The mixture was purified by preparative HPLCto give the title compound (183 mg) as a white solid. LCMS m/z=405.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 0.38 (td, J=4.7, 3.3 Hz, 1H), 0.99 (s,9H), 1.23 (td, J=8.0, 4.8 Hz, 1H), 2.24-2.31 (m, 1H), 2.71-2.75 (m, 1H),2.88 (dd, J=16.7, 1.8 Hz, 1H), 3.03 (dd, J=16.7, 6.4 Hz, 1H), 5.02 (d,J=9.5 Hz, 1H), 7.15-7.20 (m, 2H), 7.59 (td, J=7.7, 1.8 Hz, 1H), 7.99(dd, J=4.0, 1.4 Hz, 1H), 8.18 (d, J=9.5 Hz, 1H), 8.28 (d, J=4.2 Hz, 1H),8.61-8.62 (m, 1H), 8.92-8.93 (m, 1H).

Example 1.37 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((R)-2,2-Dimethyl-1-pyridin-2-yl-propyl)-amide (Compound 766)

To a solution of Intermediate 5 (200 mg, 0.774 mmol),(R)-2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine (127 mg, 0.774 mmol),and triethylamine (0.216 mL, 1.549 mmol) in DMF (3 mL) was added HATU(324 mg, 0.852 mmol). The reaction was stirred at 23° C. for 1 h thendiluted with DMSO (2 mL). The mixture was purified by preparative HPLCto give the title compound (230 mg) as a white solid. LCMS m/z=405.4[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.50 (td, J=4.8, 3.3 Hz, 1H), 0.99 (s,9H), 1.26 (td, J=7.8, 4.9 Hz, 1H), 2.24-2.30 (m, 1H), 2.69-2.74 (m, 1H),2.94-2.95 (m, 2H), 5.02 (d, J=9.5 Hz, 1H), 7.15-7.20 (m, 2H), 7.59 (td,J=7.7, 1.9 Hz, 1H), 7.99 (dd, J=4.2, 1.5 Hz, 1H), 8.18 (d, J=9.5 Hz,1H), 8.28 (d, J=4.2 Hz, 1H), 8.61-8.63 (m, 1H), 8.92-8.93 (m, 1H).

Example 1.38 Preparation of (1aS,5aS)-(S)-2-Amino-3-methyl-butyric Acid(S)-3,3-Dimethyl-2-{[2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butylEster (Compound 848)

Step A: Preparation of(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide

To a solution of Intermediate 4 (1.4 g, 5.78 mmol) and triethylamine(1.611 mL, 11.56 mmol) in DMF (15 mL) was added HATU (2.242 g, 5.90mmol). The reaction was stirred at 23° C. for 5 min, then(S)-2-amino-3,3-dimethylbutan-1-ol (0.711 g, 6.07 mmol) was added. Thereaction was stirred at 23° C. for 15 min then concentrated. The residuewas purified by silica gel column chromatography to give the titlecompound (1.97 g) as a white solid. LCMS m/z=342.2 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ 0.48 (td, J=4.6, 3.4 Hz, 1H), 1.05 (s, 9H), 1.24 (td,J=8.0, 4.7 Hz, 1H), 2.26-2.32 (m, 1H), 2.74-2.78 (m, 1H), 2.94 (d,J=16.8 Hz, 1H), 3.01 (dd, J=16.7, 6.1 Hz, 1H), 3.67-3.72 (m, 1H),3.93-3.98 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 8.42 (dd, J=1.4, 0.9 Hz, 1H),8.51 (d, J=2.7 Hz, 1H), 9.26 (d, J=1.1 Hz, 1H).

Step B: Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide

To a solution of(1aS,5aS)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (900 mg, 2.64 mmol)in chloroform (10 mL) was added 3-chlorobenzoperoxoic acid (1772 mg,7.91 mmol). The reaction was stirred at 23° C. for 3 h. Another 1.2 gmCPBA was added and stirring was continued at room temperature for 18 h.The mixture was purified by silica gel column chromatography to give thetitle compound (550 mg) as a white solid. LCMS m/z=358.3 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 0.49 (td, J=4.6, 3.3 Hz, 1H), 1.03 (s, 9H), 1.27 (td,J=8.0, 4.9 Hz, 1H), 2.08 (bs, 1H), 2.27-2.33 (m, 1H), 2.71-2.76 (m, 1H),2.93 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.7, 6.1 Hz, 1H), 3.65-3.71 (m,1H), 3.92-3.97 (m, 2H), 6.97 (d, J=8.5 Hz, 1H), 7.99 (dd, J=4.0, 1.4 Hz,1H), 8.28 (d, J=4.2 Hz, 1H), 8.78 (dd, J=1.4, 0.8 Hz, 1H).

Step C: Preparation of (S)-2-tert-Butoxycarbonylamino-3-methyl-butyricAcid(S)-3,3-Dimethyl-2-{[(1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butylEster

To a solution of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (500 mg, 1.399mmol), (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (1003 mg,4.62 mmol), triethylamine (1.170 mL, 8.39 mmol), and DMAP (68.4 mg,0.560 mmol) in 1,2-dichloroethane (10 mL) was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine. Themixture was stirred at 60° C. for 2 h. The mixture was purified bysilica gel column chromatography to give the title compound (495 mg) asa white solid. LCMS m/z=557.5.

Step D: Preparation of (1aS,5aS)-(S)-2-Amino-3-methyl-butyric Acid(S)-3,3-Dimethyl-2-{[2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butylEster

To (S)-2-tert-butoxycarbonylamino-3-methyl-butyric acid(S)-3,3-dimethyl-2-{[(1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butylester (495 mg, 0.889 mmol) was added HCl (4 M in dioxane, 5.56 mL, 22.23mmol). The reaction was stirred at 23° C. for 1 h then concentrated. Theoff-white solid was taken up in 2:1 water/acetonitrile (10 mL) thenfreeze-dried to give the HCl salt of the title compound (437 mg) as awhite solid. LCMS m/z=457.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 0.44(td, J=4.4, 3.4 Hz, 1H), 0.78 (d, J=7.0 Hz, 3H), 0.81 (d, J=7.1 Hz, 3H),0.97 (s, 9H), 1.27 (td, J=7.8, 4.7 Hz, 1H), 1.98-2.06 (m, 1H), 2.27-2.33(m, 1H), 2.65-2.69 (m, 1H), 2.73-2.84 (m, 2H), 3.85 (d, J=4.2 Hz, 1H),4.12 (td, J=10.2, 2.3 Hz, 1H), 4.33 (dd, J=8.2, 2.9 Hz, 1H), 4.47 (t,J=10.9 Hz, 1H), 8.08 (d, J=9.7 Hz, 1H), 8.29 (dd, J=4.2, 1.5 Hz, 1H),8.33 (s, 3H), 8.48 (d, J=4.2 Hz, 1H), 9.11-9.12 (m, 1H).

Example 1.39 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((R)-1,2-Dimethyl-propyl)-amide (Compound 912)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 5 and (R)-3-methylbutan-2-amine. LCMSm/z=328.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.46-0.50 (m, 1H), 0.96 (d,J=6.8 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H), 1.19 (d, J=6.9 Hz, 3H), 1.26 (td,J=8.2, 4.8 Hz, 1H), 1.75-1.87 (m, 1H), 2.26-2.33 (m, 1H), 2.70-2.75 (m,1H), 2.94 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.6, 6.0 Hz, 1H), 3.95-4.05(m, 1H), 6.64 (d, J=9.0 Hz, 1H), 7.98 (dd, J=4.0, 1.4 Hz, 1H), 8.28 (d,J=4.0 Hz, 1H), 8.78-8.80 (m, 1H).

Example 1.40 Preparation of(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((R)-1,2-Dimethyl-propyl)-amide (Compound 828)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 6 and (R)-3-methylbutan-2-amine. LCMSm/z=328.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.44-0.48 (m, 1H), 0.95 (d,J=6.8 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H), 1.18 (d, J=6.9 Hz, 3H), 1.26 (td,J=8.0, 4.9 Hz, 1H), 1.75-1.88 (m, 1H), 2.26-2.33 (m, 1H), 2.70-2.75 (m,1H), 2.93 (d, J=17.1 Hz, 1H), 3.02 (dd, J=16.7, 6.2 Hz, 1H), 3.95-4.05(m, 1H), 6.64 (d, J=8.9 Hz, 1H), 7.98 (dd, J=4.0, 1.4 Hz, 1H), 8.28 (d,J=4.0 Hz, 1H), 8.79-8.80 (m, 1H).

Example 1.41 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Fluoro-1,1-dimethyl-ethyl)-amide (Compound 904)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 5 and 1-fluoro-2-methylpropan-2-amine. LCMSm/z=332.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.44-0.48 (m, 1H), 1.27 (td,J=8.0, 5.0 Hz, 1H), 1.46 (s, 3H), 1.47 (s, 3H), 2.26-2.34 (m, 1H),2.703-2.76 (m, 1H), 2.91 (d, J=16.9 Hz, 1H), 3.00 (dd, J=16.6, 6.2 Hz,1H), 4.54 (d, J=47.5 Hz, 2H), 6.73 (s, 1H), 7.98 (dd, J=4.0, 1.5 Hz,1H), 8.28 (d, J=4.2 Hz, 1H), 8.78-8.79 (m, 1H).

Example 1.42 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-2-Hydroxy-1-phenyl-ethyl)-amide (Compound 913)

The title compound was prepared in a manner similar to that described inMethod UU using Intermediate 5 and (S)-2-amino-2-phenylethanol. LCMSm/z=378.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.43-0.47 (m, 1H), 1.26 (td,J=7.8, 4.9 Hz, 1H), 2.26-2.33 (m, 1H), 2.55 (bs, 1H), 2.70-2.76 (m, 1H),2.90 (d, J=16.9 Hz, 1H), 3.00 (dd, J=16.7, 6.3 Hz, 1H), 3.95-4.04 (m,2H), 5.18-5.24 (m, 1H), 7.29-7.35 (m, 1H), 7.36-7.41 (m, 4H), 7.44 (d,J=7.4 Hz, 1H), 7.98 (dd, J=4.2, 1.5 Hz, 1H), 8.28 (d, J=4.2 Hz, 1H),8.80 (d, J=1.1 Hz, 1H).

Example 1.43 Preparation of(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Fluoromethyl-2,2-dimethyl-propyl)-amide (Compound 918)

The title compound was prepared in a manner similar to that described inMethod UU, using Intermediate 6 and(S)-1-fluoro-3,3-dimethylbutan-2-amine hydrochloride. LCMS m/z=360.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.50 (td, J=4.6 and 3.2 Hz, 1H), 1.05(s, 9H), 1.25-1.30 (m, 1H), 2.27-2.35 (m, 1H), 2.72-2.77 (m, 1H), 2.93(d, J=16.9 Hz, 1H), 3.01 (dd, J=16.6 and 6.2 Hz, 1H), 4.03-4.15 (m, 1H),4.48-4.74 (m, 2H), 7.04 (d, J=10.0 Hz, 1H), 7.99 (dd, J=4.1 and 1.5 Hz,1H), 8.28 (d, J=4.1 Hz, 1H), 8.81 (d, J=1.5 Hz, 1H).

Example 1.44 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Fluoromethyl-cyclobutyl)-amide (Compound 924)

The title compound was prepared in a manner similar to that described inMethod UU, using Intermediate 5 and 1-(fluoromethyl)cyclobutanaminehydrochloride, which was prepared in a similar manner to that describedin Example 1.58, Step A to Step E, using (1-aminocyclobutyl)methanol.LCMS m/z=344.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.48 (td, J=4.6 and 3.2Hz, 1H), 1.24-1.29 (m, 1H), 1.85-1.95 (m, 1H), 2.00-2.10 (m, 1H),2.27-2.47 (m, 5H), 2.70-2.75 (m, 1H), 2.91 (d, J=17.3 Hz, 1H), 3.00 (dd,J=16.7 and 6.2 Hz, 1H), 4.68 (d, J=47.8 Hz, 2H), 6.98 (s, 1H), 7.97 (dd,J=4.1 and 1.5 Hz, 1H), 8.28 (dd, J=4.1 and 0.7 Hz, 1H), 8.80 (dd, J=1.5and 0.7 Hz, 1H).

Example 1.45 Preparation of(1aR,5aR)-2-(4-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1,1-dimethyl-ethyl)-amide (Compound 931)

Step A: Preparation of 2-Hydrazinyl-4-iodopyridine

To a solution of 2-fluoro-4-iodopyridine (7.00 g, 31.4 mmol) in ethanol(60 mL) was added hydrazine monohydrate (15.23 mL, 314 mmol). Themixture was stirred at 40° C. for 15 h then concentrated. The resultingresidue was triturated with 1:1 hexanes/ether. The remaining solid wasfurther triturated with water then dried under vacuum to give the titlecompound (6.6 g) as a tan solid. LCMS m/z=235.9 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 4.15 (s, 2H), 6.86 (dd, J=5.2, 1.5 Hz, 1H), 7.13 (d, J=1.5Hz, 1H), 7.56 (s, 1H), 7.67 (d, J=5.3 Hz, 1H).

Step B: Preparation of(1aR,5aR)-2-(4-Iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid Ethyl Ester

To a solution of (1R,5S)-bicyclo[3.1.0]hexan-2-one (2.045 g, 21.27 mmol)and diethyl oxalate (2.91 mL, 21.27 mmol) in absolute ethanol (100 mL)was added a 1.0 M THF solution of potassium 2-methylpropan-2-olate(21.27 mL, 21.27 mmol). The mixture was stirred at 40° C. for 4 h.2-Hydrazinyl-4-iodopyridine (5.00 g, 21.27 mmol) was added followed by a3.0 M aqueous solution of hydrogen chloride (21.27 mL, 63.8 mmol). Thereaction was stirred at 45° C., for 16 h. Brine (150 mL) was added. Themixture was extracted with dichloromethane (3×50 mL). The combinedorganic extracts were washed with brine (100 mL), dried (MgSO₄),filtered, and then concentrated. The residue was purified by silica gelflash chromatography to give the title compound (5.8 g) as a whitesolid. LCMS m/z=396.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.44 (td, J=4.7,3.5 Hz, 1H), 1.25 (td, J=8.0, 5.1 Hz, 1H), 1.40 (t, J=7.1 Hz, 3H),2.22-2.29 (m, 1H), 2.80-2.85 (m, 1H), 2.85 (d, J=17.1 Hz, 1H), 2.97 (dd,J=16.9, 6.6 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 7.57 (dd, J=5.2, 1.4 Hz,1H), 8.10 (d, J=5.2 Hz, 1H), 8.48 (s, 1H).

Step C: Preparation of(1aR,5aR)-2-(4-Iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid

To a solution of(1aR,5aR)-2-(4-iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ethyl ester in MeOH (10.00 mL) and THF (10.00 mL) was added a 2 Maqueous solution of sodium hydroxide (5.20 mL, 10.40 mmol). The mixturewas stirred at room temperature for 2 h then concentrated. The remainingsolid was dissolved in water (30 mL). The solution was acidified to pH˜2 by addition of 6 M aqueous HCl. The resulting precipitate wascollected by filtration, rinsed with water, then dried to give the titlecompound (190 mg) as a white solid. LCMS m/z=368.1 [M+H]⁺.

Step D: Preparation of(1aR,5aR)-2-(4-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid

To a solution of(1aR,5aR)-2-(4-iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (174 mg, 0.47 mmol) in DMSO (2.5 mL) was added cesium fluoride (500mg, 3.29 mmol). The mixture was heated under microwave irradiation at200° C. for 60 min. The mixture was purified by preparative HPLC to givethe title compound as a white solid (85 mg). LCMS m/z=260.1 [M+H]⁺.

Step E: Preparation of(1aR,5aR)-2-(4-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1,1-dimethyl-ethyl)-amide

To a solution of(1aR,5aR)-2-(4-fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (68 mg, 0.262 mmol), 2-amino-2-methylpropan-1-ol (23.38 mg, 0.262mmol), and triethylamine (0.073 mL, 0.525 mmol) in DMF (1 mL) was addedHATU (105 mg, 0.275 mmol). The reaction was stirred at 23° C. for 20 minthen concentrated. The residue was purified by silica gel columnchromatography to give the title compound (80 mg) as a white solid. LCMSm/z=331.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.46 (td, J=4.6, 3.4 Hz,1H), 1.26 (td, J=7.8, 4.9 Hz, 1H), 1.41 (s, 3H), 1.42 (s, 3H), 2.24-2.30(m, 1H), 2.79-2.84 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.6,6.3 Hz, 1H), 3.70 (d, J=6.4 Hz, 2H), 4.69 (t, J=6.3 Hz, 1H), 6.93-6.98(m, 2H), 7.63 (dd, J=10.1, 2.4 Hz, 1H), 8.43 (dd, J=8.5, 5.7 Hz, 1H).

Example 1.46 Preparation of1-(2,4-Difluoro-phenyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylicAcid (2-Hydroxy-1,1-dimethyl-ethyl)-amide (Compound 515)

The title compound was prepared in a manner similar to that described inMethod X using 2-amino-2-methylpropan-1-ol. LCMS m/z=348.2 [M+H]⁺.

Example 1.47 Preparation of(1aR,5aR)-2-(5-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1,1-dimethyl-ethyl)-amide (Compound 151)

The title compound was prepared in a manner similar to that described inMethod G using 2-amino-2-methylpropane-1,3-diol and(1aR,5aR)-2-(5-Chloropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid. The aforementioned acid was prepared in a similar method asdescribed in Method A and B using (1R,5S)-bicyclo[3,1,0]hexan-2-one and5-chloro-2-hydrazinylpyridine. LCMS m/z=347.2 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.25 (td, J=8.3, 4.4 Hz, 1H),1.406 (s, 3H), 1.410 (s, 3H), 2.24-2.30 (m, 1H), 2.75-2.80 (m, 1H), 2.90(d, J=16.6 Hz, 1H), 3.00 (dd, J=16.6, 6.4 Hz, 1H), 3.70 (s, 2H), 4.63(bs, 1H), 6.92 (s, 1H), 7.78 (dd, J=8.7, 2.5 Hz, 1H), 7.87 (dd, J=8.8,0.6 Hz, 1H), 8.41 (dd, J=2.5, 0.6 Hz, 1H).

Example 1.48 Preparation of(1aR,5aR)-2-(2,4-Dichloro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (1-Hydroxymethyl-cyclopropyl)-amide (Compound 174)

The title compound was prepared in a manner similar to that described inMethod G using(1aR,5aR)-2-(2,4-dichloro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid and (1-hydroxymethyl-cyclopropyl)-amine. LCMS m/z=378.2 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 0.51 (td, J=4.6 and 3.4 Hz, 1H), 0.90-1.03(m, 4H), 1.14-1.21 (m, 1H), 2.00-2.07 (m, 1H), 2.27-2.37 (m, 1H), 2.97(d, J=16.6 Hz, 1H), 3.06 (dd, J=16.6 and 6.3 Hz, 1H), 3.71 (s, 2H), 7.28(bs, 1H), 7.40 (dd, J=8.5 and 2.1 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.58(d, J=2.1 Hz, 1H).

Example 1.49 Preparation of(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid tert-Butylamide (Compound 593)

The title compound was prepared in a manner similar to that described inMethod G using Intermediate 2 and tert-butyl amine. LCMS m/z=298.3[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.47 (td, J=4.6 and 3.3 Hz, 1H),1.22-1.27 (m, 1H), 1.48 (s, 9H), 2.25-2.32 (m, 1H), 2.71-2.76 (m, 1H),2.93 (d, J=16.7 Hz, 1H), 3.02 (dd, J=16.6 and 6.2 Hz, 1H), 6.79 (s, 1H),8.42 (br, 1H), 8.49 (d, J=2.0 Hz, 1H), 9.25 (s, 1H).

Example 1.50 Preparation of(1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Hydroxy-1,1-dimethyl-ethyl)-amide (Compound 644)

The title compound was prepared in a manner similar to that described inMethod T using(1aR,5aR)-2-(5-bromo-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-amide and dicyanozinc. LCMSm/z=338.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.47 (dd, J=4.6 and 3.4Hz, 1H), 1.25-1.31 (m, 1H), 1.45 (s, 6H), 2.26-2.34 (m, 1H), 2.78-2.84(m, 1H), 2.93 (d, J=16.1 Hz, 1H), 3.02 (dd, J=16.7 and 6.3 Hz, 1H), 3.73(s, 2H), 6.93-6.97 (bs, 1H), 7.43 (dd, J=5.0 and 1.2 Hz, 1H), 8.17 (s,1H), 8.63 (d, J=5.0, 1H).

Example 1.51 Preparation of(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Hydroxymethyl-2-methyl-propyl)-amide (Compound 690)

The title compound was prepared in a manner similar to that described inMethod CCC. LCMS m/z=344.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.47(dd, J=8.0 and 4.7 Hz, 1H), 1.02 (t, J=7.2 Hz, 6H), 1.28 (td, J=8.0 and5.0 Hz, 1H), 2.00-2.05 (m, 1H), 2.28-2.32 (m, 1H), 2.72-2.77 (m, 1H),2.95 (d, J=17.3 Hz, 1H), 3.02 (dd, J=16.7 and 6.3 Hz, 1H), 3.73-3.89 (m,3H), 6.98 (d, J=8.3 Hz, NH, 1H), 7.99 (dd, J=4.1 and 1.5 Hz, 1H), 8.28(d, J=4.1 Hz, 1H), 8.80 (s, 1H).

Example 1.52 Preparation of(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-2,2-Dimethyl-1-methylcarbamoyl-propyl)-amide (Compound 704)

The title compound was prepared in a manner similar to that described inMethod CCC. LCMS m/z=385.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.44(dd, J=8.0 and 4.7 Hz, 1H), 1.24-1.29 (m, 1H), 2.26-2.32 (m, 1H),2.72-2.77 (m, 1H), 2.82 (d, J=4.8 Hz, 3H), 2.88 (d, J=16.7 Hz, 1H), 3.01(dd, J=16.5 and 6.5 Hz, 1H), 4.30 (d, J=9.5 Hz, 1H), 5.90 (q, J=4.4 Hz,NH, 1H), 7.44 (d, J=9.5 Hz, NH, 1H), 8.00 (dd, J=4.1 and 1.5 Hz, 1H),8.28 (d, J=4.1 Hz, 1H), 8.84 (s, 1H).

Example 1.53 Preparation of(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-Methylcarbamoyl-phenyl-methyl)-amide (Compound 722)

(S)-2-Amino-N-methyl-2-phenylacetamide was prepared in a manner similarto that described in Method HHH and III using(S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid and methylamine.The title compound was prepared in a manner similar to that described inMethod G using(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid and (S)-2-amino-N-methyl-2-phenylacetamide. LCMS m/z=405.3 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 0.40-0.47 (m, 1H), 1.21-1.29 (m, 1H),2.23-2.31 (m, 1H), 2.69-2.75 (m, 1H), 2.83 (dd, J=4.9 and 1.9 Hz, 3H),2.87 (d, J=16.9 Hz, 1H), 2.92-3.00 (m, 1H), 5.50 (d, J=6.8 Hz, 1H), 5.69(bs, 1H), 7.30-7.41 (m, 3H), 7.43-7.48 (m, 2H), 7.97 (dd, J=4.0 and 1.4Hz, 1H), 7.98-8.03 (m, 1H), 8.26 (d, J=4.0 Hz, 1H), 8.83-8.85 (m, 1H).

Example 1.54 Preparation of(S)-3,3-Dimethyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyricAcid Methyl Ester (Compound 746)

The title compound was prepared in a manner similar to that described inMethod CCC, using(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid and (S)-methyl 2-amino-3,3-dimethylbutanoate. LCMS m/z=386.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.44 (dd, J=8.0 and 4.7 Hz, 1H),1.06 (s, 9H), 1.24-1.29 (m, 1H), 2.26-2.32 (m, 1H), 2.72-2.77 (m, 1H),2.90 (d, J=16.8 Hz, 1H), 3.02 (dd, J=16.7 and 6.4 Hz, 1H), 3.75 (s, 3H),4.58 (d, J=9.6 Hz, 1H), 7.28 (d, J=9.6 Hz, NH, 1H), 8.00 (dd, J=4.1 and1.4 Hz, 1H), 8.29 (d, J=4.1 Hz, 1H), 8.83 (d, J=1.3 Hz, 1H).

Example 1.55 Preparation of(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl)-amide (Compound889)

Step A: Preparation of Methyl2-Aamino-3-fluoro-2-(fluoromethyl)propanoate

The title compound was prepared as described in Synthesis 1994 vol. 7pp. 701-702.

Step B: Preparation of2-{[(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-3-fluoro-2-fluoromethyl-propionicAcid Methyl Ester

To a solution of(1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (100 mg, 0.363 mmol), methyl2-amino-3-fluoro-2-(fluoromethyl)propanoate hydrochloride (76 mg, 0.399mmol) and triethylamine (0.101 mL, 0.725 mmol) in DMF (2 mL) was addedHATU (138 mg, 0.363 mmol). The reaction was stirred at 50° C. for 2 h,then concentrated. The residue was purified by silica gel flashchromatography to give the title compound as a white solid. LCMSm/z=411.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.46 (td, J=4.7, 3.3 Hz,1H), 1.25 (td, J=7.8, 4.7 Hz, 1H), 2.24-2.30 (m, 1H), 2.79-2.84 (m, 1H),2.89 (d, J=16.8 Hz, 1H), 2.99 (dd, J=16.4, 6.2 Hz, 1H), 3.89 (s, 3H),4.81-5.12 (m, 4H), 7.22 (dd, J=5.3, 1.8 Hz, 1H), 7.51 (s, 1H), 7.98 (d,J=1.8 Hz, 1H), 8.36 (d, J=5.3 Hz, 1H).

Step C: Preparation of(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid (2-Fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl)-amide

To a solution of2-{[(1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-3-fluoro-2-fluoromethyl-propionicacid methyl ester (130 mg, 0.316 mmol) in THF (2 mL) and MeOH (0.200 mL)was added sodium borohydride (23.94 mg, 0.633 mmol). The reaction wasstirred at 23° C. for 2 h. Saturated aqueous NaHCO₃ (15 mL) was added.The mixture was extracted with dichloromethane (3×15 mL). The combinedorganic extracts were dried (MgSO₄), filtered, then concentrated. Theresidue was purified by silica gel flash chromatography to give thetitle compound (106 mg) as a white solid. LCMS m/z=383.2 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 0.46 (td, J=4.6, 3.5 Hz, 1H), 1.27 (td, J=8.0, 4.9Hz, 1H), 2.25-2.31 (m, 1H), 2.80-2.85 (m, 1H), 2.89 (d, J=16.9 Hz, 1H),2.99 (dd, J=16.6, 6.3 Hz, 1H), 3.96 (d, J=5.9 Hz, 2H), 4.25 (t, J=6.8Hz, 1H), 4.55-4.84 (m, 4H), 7.23 (dd, J=5.3, 1.8 Hz, 1H), 7.27 (s, 1H),7.92 (d, J=1.6 Hz, 1H), 8.36 (d, J=5.3 Hz, 1H).

Example 1.56 Preparation of(1aS,5aS)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-3,3,3-Trifluoro-1-hydroxymethyl-propyl)-amide (Compound 891)

Step A: Preparation of(1aS,5aS)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid

To a solution of(1aS,5aS)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ethyl ester (1.00 g, 2.87 mmol) in methanol (5 mL) and THF (5.00mL) was added a 2.0 M aqueous solution of sodium hydroxide (2.87 mL,5.74 mmol). The reaction was stirred at 23° C. for 2 h. The organicsolvents were removed by distillation. The remaining aqueous solutionwas diluted with water (20 mL) then acidified to pH ˜2 by addition of 6M aq. HCl. The resulting precipitate was collected by filtration, rinsedwith water, then dried under vacuum to give the title compound (0.87 g)as a white solid. LCMS m/z=320.0 [M+H]⁺.

Step B: Preparation of(1aS,5aS)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid

(1aS,5aS)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (0.87 g, 2.72 mmol) was dissolved in DMA (10 mL). Sodium hydride(0.109 g, 2.72 mmol) was added, and nitrogen was bubbled through themixture for 10 min. Zinc(II) cyanide (0.638 g, 5.44 mmol) and palladiumtetrakistriphenylphosphine (0.157 g, 0.136 mmol) were added. Thereaction was stirred under microwave heating in a sealed tube at 120° C.for 2 h. Water (25 mL) and 6 M aqueous HCl (1 mL) were added. Themixture was extracted with 25% iPrOH/dichloromethane (3×25 mL) (Thebiphasic mixture was filtered after the first extraction to clear up anemulsion). The combined organic extracts were dried (MgSO₄), filtered,then concentrated. The residue was purified by flash chromatography togive the title compound (0.68 g) as a tan solid. LCMS m/z=267.0 [M+H]⁺.

Step C: Preparation of (S)-2-Amino-4,4,4-trifluorobutan-1-ol

To an ice-cooled solution of(S)-2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (1.0 g,3.89 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.813 mL, 4.67 mmol)in THF (15 mL) was added dropwise ethyl chloroformate (0.409 mL, 4.28mmol). The cooling bath was removed and the mixture was stirred at 23°C. for 2 h. The mixture was filtered to remove the white precipitate,and the filtrate was treated with a 2 M THF solution of lithiumborohydride (1.944 mL, 3.89 mmol) resulting in vigorous gas evolution.The mixture was stirred at room temperature for 2 h. Brine (25 mL) wasadded. The mixture was extracted with ethyl acetate (3×25 mL). Thecombined organic extracts were dried (MgSO₄), filtered, thenconcentrated under vacuum. The residue was purified by silica gel flashchromatography to give (S)-tert-butyl4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (0.80 g) as a white solid.This solid was treated with 4 M HCl in dioxane (10 mL) for 60 min thenconcentrated to give the HCl salt of the title compound (0.54 g) as awhite solid. ¹H NMR (400 MHz, CD₃OD) δ 2.55-2.79 (m, 2H), 3.42 (bs, 1H),3.54 (dd, J=11.6, 5.6 Hz, 1H), 3.66 (dd, J=11.6, 3.9 Hz, 1H), 3.53 (bs,1H), 8.27 (bs, 3H).

Step D: Preparation of(1aS,5aS)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-3,3,3-Trifluoro-1-hydroxymethyl-propyl)-amide

To a solution of(1aS,5aS)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (75 mg, 0.282 mmol) and triethylamine (0.118 mL, 0.845 mmol) in DMF(1 mL) was added HATU (118 mg, 0.310 mmol). The reaction was stirred at23° C., for 5 min, then was added (S)-2-amino-4,4,4-trifluorobutan-1-olhydrochloride (55.6 mg, 0.310 mmol). The reaction was stirred at 23° C.for 30 min, then concentrated. The residue was purified by silica gelflash chromatography to give the title compound (86 mg) as a whitesolid. LCMS m/z=392.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.47 (td, J=4.7,3.2 Hz, 1H), 1.27 (td, J=8.1, 4.8 Hz, 1H), 2.26-2.32 (m, 1H), 2.54-2.69(m, 3H), 2.77-2.82 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.6,6.1 Hz, 1H), 3.88 (d, J=2.9 Hz, 2H), 4.33-4.41 (m, 1H), 7.23 (d, J=8.2Hz, 1H), 7.41 (dd, J=5.1, 1.4 Hz, 1H), 8.17 (t, J=0.8 Hz, 1H), 8.62 (dd,J=5.1, 0.6 Hz, 1H).

Example 1.57 Preparation of(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide (Compound 629)

To a solution of(1aR,5aR)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (1.024 g, 3.0 mmol)in formic acid (10 mL) was added hydrogen peroxide (35% in water, 0.582mL, 6.00 mmol). The reaction was stirred at 45° C. for 72 h andconcentrated. The residue was dissolved in THF/MeOH (40 mL/40 mL) andadded lithium hydroxide (1.437 g, 60.0 mmol) in water (5 mL). Thereaction was stirred at room temperature for 1 h and neutralized withNH₄Cl solution. After removal of the organic solvent, the mixture wasextracted with EtOAc. The organics were purified by silica gel columnchromatography. The resulting oil was treated with ACN (5 mL) andconcentrated to give the title compound (0.49 g) as a white solid. LCMSm/z=358.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.47 (dd, J=8.0 and 4.7Hz, 1H), 1.05 (s, 9H), 1.28 (td, J=7.9 and 5.0 Hz, 1H), 2.28-2.32 (m,1H), 2.72-2.76 (m, 1H), 2.92 (d, J=17.0 Hz, 1H), 3.02 (dd, J=16.7 and6.4 Hz, 1H), 3.67 (dd, J=11.9 and 8.8 Hz, 1H), 3.92-3.98 (m, 2H), 6.97(d, J=8.7 Hz, NH, 1H), 8.00 (dd, J=4.1 and 1.5 Hz, 1H), 8.28 (d, J=4.1Hz, 1H), 8.79 (s, 1H).

Example 1.58 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Fluoromethyl-2,2-dimethyl-propyl)-amide (Compound 916) StepA: Preparation of (S)-2-(Benzylamino)-3,3-dimethylbutan-1-ol

(S)-2-Amino-3,3-dimethylbutan-1-ol (4.01 g, 34.2 mmol) was dissolved inbenzene (120 mL). Benzaldehyde (3.65 mL, 35.9 mmol) and p-TsOHmonohydrate (1.302 mg, 6.84 μmol) were added. The reaction mixture washeated at reflux for 5 h using Dean-Stark to remove water, the mixturewas then concentrated. The residue was dissolved in anhydrous MeOH (100mL), cooled down in an ice-water bath, and added sodium borohydride(1.942 g, 51.3 mmol) slowly. The reaction mixture was stirred for 30min, quenched with 1 N NaOH solution, diluted with water, and extractedwith ethyl acetate. The combined organics were washed with water, driedover anhydrous Na₂SO₄, filtered, then concentrated to give the titlecompound (5.77 g) as a colorless oil without further purification. LCMSm/z=208.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.88 (s, 9H), 2.33 (dd,J=6.4 and 4.7 Hz, 1H), 3.34 (dd, J=10.6 and 6.4 Hz, 1H), 3.59 (dd,J=10.6 and 4.7 Hz, 1H), 3.76 and 3.85 (dd, J=12.8 Hz, 2H), 7.20-7.27 (m,5H).

Step B: Preparation of(4S)-4-(tert-Butyl)-3-(phenylmethyl)-1,2,3-oxathiazolidine-2-oxide

(S)-2-(Benzylamino)-3,3-dimethylbutan-1-ol (5.77 g, 27.8 mmol) in dryDCM (100 mL) was cooled down to −20° C., DIEA (19.39 ml, 111 mmol) wasadded, followed by thionyl chloride (2.228 ml, 30.6 mmol) in DCM (10mL). The reaction mixture was stirred for 1 h at this temperature, thenconcentrated. The residue was purified by column chromatography to givethe title compound (6.26 g) as a diastereomeric mixture. LCMS m/z=254.0[M+H]⁺.

Step C: Preparation of(4S)-4-(tert-Butyl)-3-(phenylmethyl)-1,2,3-oxathiazolidine-2,2-dioxide

To a solution of(4S)-4-(tert-butyl)-3-(phenylmethyl)-1,2,3-oxathiazolidine-2-oxide (6.26g, 24.71 mmol) in acetonitrile (30 mL) and water (30 mL) at 0° C. wasadded ruthenium chloride hydrate (5.13 mg, 0.025 mmol), followed bysodium periodate (7.93 g, 37.1 mmol). The reaction mixture was slowlywarmed to room temperature and stirred for 3 h, diluted with water,extracted with ethyl acetate. The combined organics were washed withwater, dried over anhydrous Na₂SO₄, filtered then concentrated to givethe title compound (6.22 g) as an off-white solid. LCMS m/z=270.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 1.00 (s, 9H), 3.25-3.30 (m, 1H),4.31-4.40 (m, 2H), 4.47 and 4.55 (dd, J=15.2 Hz, 2H), 7.30-7.48 (m, 5H).

Step D: Preparation of (S)—N-Benzyl-1-fluoro-3,3-dimethylbutan-2-amine

To a solution of(4S)-4-(tert-butyl)-3-(phenylmethyl)-1,2,3-oxathiazolidine-2,2-dioxide(6.22 g, 23.09 mmol) in THF (100 mL) was added a 1 M solution oftetrabutylammonium fluoride in THF (46.2 ml, 46.2 mmol) at 0° C. Thereaction mixture was warmed to room temperature and stirred overnight.Solvent was evaporated, and ether (50 mL) and 20% H₂SO₄ aqueous solution(20 mL) were added. The reaction mixture was stirred for 2 h at roomtemperature, diluted with water, neutralized with solid NaHCO₃ slowlythen extracted with ethyl acetate. The combined organics were dried overanhydrous Na₂SO₄, filtered, then concentrated. The residue was purifiedby column chromatography to give the title compound (4.13 g) as a lightyellow oil. LCMS m/z=210.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.96 (s,9H), 2.41 (dt, J=24.7 and 4.3 Hz, 1H), 3.76 (d, J=13.1 Hz, 1H), 4.01 (d,J=13.1 Hz, 1H), 4.39-4.72 (m, 2H), 7.23-7.38 (m, 5H).

Step E: Preparation of (S)-1-Fluoro-3,3-dimethylbutan-2-amineHydrochloride

To a solution of (S)—N-benzyl-1-fluoro-3,3-dimethylbutan-2-amine (4.12g, 19.68 mmol) in methanol (50 mL) was added 10% palladium on carbon(2.095 g, 1.968 mmol). The reaction mixture was shaken under H₂atmosphere (60 Psi) for 24 h, a 1.25 M solution of HCl in ethanol (31.5mL, 39.4 mmol) was added. The reaction mixture was stirred at roomtemperature for 1 h. The solid was filtered through Celite, washed withmethanol. The filtrate was concentrated to give the title compound (3.1g). ¹H NMR (400 MHz, DMSO-d₆) δ 0.96 (s, 9H), 3.11-3.20 (m, 1H),4.55-4.82 (m, 2H), 8.26 (s, 3H).

Step F: Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Fluoromethyl-2,2-dimethyl-propyl)-amide

The title compound was prepared in a manner similar to that described inMethod UU, using Intermediate 5 and(S)-1-fluoro-3,3-dimethylbutan-2-amine hydrochloride. LCMS m/z=360.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 0.50 (td, J=4.6 and 3.2 Hz, 1H), 1.05(s, 9H), 1.25-1.30 (m, 1H), 2.27-2.35 (m, 1H), 2.72-2.77 (m, 1H), 2.95(dt, J=16.8 and 0.7 Hz, 1H), 3.01 (dd, J=16.6 and 5.8 Hz, 1H), 4.03-4.15(m, 1H), 4.48-4.74 (m, 2H), 7.04 (d, J=10.1 Hz, 1H), 7.99 (dd, J=4.1 and1.5 Hz, 1H), 8.28 (dd, J=4.1 and 0.6 Hz, 1H), 8.80 (dd, J=1.5 and 0.7Hz, 1H).

Example 1.59 Preparation of(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicAcid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide (Compound 699,Anhydrous Form)

To a 4 L reactor equipped with an overhead stirrer, chiller/heater, anda dropping funnel was added(1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (Compound 699, 145g, 406 mmol), acetonitrile (205 mL, 3925 mmol), and water (290 mL). Themixture was heated to 60° C. and then stirred for 60 min. To theresulting reaction was added an additional amount of water (2900 mL),cooled to 0° C., and allowed to stir for 4 h. The mixture was filtered,the solids washed with water and dried under vacuum at 50° C. to provideCompound 699 as the anhydrous form, the material was characterized byPXRD (FIG. 16), DSC/TGA (FIG. 17), and DMS (FIG. 18).

Example 2 Homogeneous Time-Resolved Fluorescence (HTRF®) Assay ForDirect cAMP Measurement

A: CB₂ Assay

Compounds were screened for agonists and inverse agonists of CB₂receptor (e.g., human CB₂ receptor) using the HTRF® assay for directcAMP measurement (Gabriel et al., ASSAY and Drug DevelopmentTechnologies, 1:291-303, 2003) in recombinant CHO-K1 cells stablytransfected with the CB₂ receptor. CHO-K1 cells were obtained from ATCC®(Manassas, Va.; Catalog #CCL-61). An agonist of the CB₂ receptor wasdetected in the HTRF® assay for direct cAMP measurement as a compoundwhich decreased cAMP concentration. An inverse agonist of the CB₂receptor was detected in the HTRF® assay for direct cAMP measurement asa compound which increased cAMP concentration. The HTRF® assay also wasused to determine EC₅₀ values for CB₂ receptor agonists and inverseagonists.

B: CB₁ Assay

Compounds were also screened for agonists and inverse agonists of theCB₁ receptor (e.g., human CB₁ receptor) using HTRF® assay for directcAMP measurement (Gabriel et al., ASSAY and Drug DevelopmentTechnologies, 1:291-303, 2003) in recombinant CHO-K1 cells stablytransfected with the CB₁ receptor. CHO-K1 cells were obtained from ATCC®(Manassas, Va.; Catalog #CCL-61). An agonist of the CB₁ receptor wasdetected in the HTRF® assay for direct cAMP measurement as a compoundwhich decreased cAMP concentration. An inverse agonist of the CB₁receptor was detected in the HTRF® assay for direct cAMP measurement asa compound which increased cAMP concentration. The HTRF® assay also wasused to determine EC₅₀ values for CB₁ receptor agonists and inverseagonists.

Principle of the Assay:

The HTRF® assay kit was purchased from Cisbio-US, Inc. (Bedford, Mass.;Catalog #62AM4PEC). The HTRF® assay supported by the kit is acompetitive immunoassay between endogenous cAMP produced by the CHO-K1cells and tracer cAMP labeled with the dye d2. The tracer binding isvisualized by a monoclonal anti-cAMP antibody labeled with Cryptate. Thespecific signal (i.e., fluorescence resonance energy transfer, FRET) isinversely proportional to the concentration of unlabeled cAMP in thestandard or sample.

Standard Curve:

The fluorescence ratio (665 nm/620 nm) of the standards (0.17 to 712 nMcAMP) included in the assay was calculated and used to generate a cAMPstandard curve according to the kit manufacturer's instructions. Thefluorescence ratio of the samples (test compound or compound buffer) wascalculated and used to deduce respective cAMP concentrations byreference to the cAMP standard curve.

Setup of the Assay:

HTRF® assay was carried out using a two-step protocol essentiallyaccording to the kit manufacturer's instructions, in 20 μL total volumeper well in 384-well plate format (ProxiPlates; PerkinElmer, Fremont,Calif.; catalog #6008280). To each of the experimental wells wastransferred 1500 recombinant CHO-K1 cells in 5 μL phosphate bufferedsaline containing calcium chloride and magnesium chloride (PBS+;Invitrogen, Carlsbad, Calif.; catalog #14040) followed by test compoundin 5 μL assay buffer (PBS+supplemented with 0.2% BSA, 4 μM forskolin and1 mM IBMX (Sigma-Aldrich, St. Louis, Mo.; catalog #s A8806, F6886 and15879 respectively). The plate was then incubated at room temperaturefor 1 h. To each well was then added 5 μL cAMP-d2 conjugate in lysisbuffer and 5 μL Cryptate conjugate in lysis buffer according to the kitmanufacturer's instructions. The plate was then further incubated atroom temperature for 1 h, after which the assay plate was read.

Assay Readout:

The HTRF® readout was accomplished using a PHERAstar (BMG Labtech Inc.,Durham, N.C.) or an EnVision™ (Perkin Elmer, Fremont Calif.) microplatereader. Certain compounds described herein had hCB₁ EC₅₀ values rangingfrom about 279 pM to about 76.47 μM in this assay and hCB₂ EC₅₀ valuesranging from about 170 pM to about 44.72 μM in this assay. Certain othercompounds described herein had hCB₂ EC₅₀ values ranging from about 94 pMto about 2.7 nM in this assay.

Example 3 PathHunter β-Arrestin Assay

A: CB₂ Assay

Compounds were screened for agonists of the human CB₂ receptor using theDiscoveRx PathHunter β-arrestin assay which measures the β-arrestinbinding to the CB₂ receptor upon its activation. CB₂ was cloned into thepCMV-PK vector (DiscoveRx, Fremont, Calif.; catalog #93-0167) andtransfected into the CHO-K1 EA-Arrestin parental cell line (DiscoveRx,Fremont, Calif.; catalog #93-0164). CHO-K1 positive clones stablyexpressing the CB₂-ProLink fusion protein were identified by theirresponses to the CB₂ agonist CP55,940. Clone #61 was chosen for its bigagonist window and homogenous expression as detected by anti-HA flowcytometry

Principle of the assay:

The PathHunter-arrestin assay measures the interaction of β-arrestinwith activated GPCRs using Enzyme Fragment Complementation (Yan et al.,J. Biomol. Screen. 7: 451-459, 2002). A small, 42 amino acidβ-galactosidase fragment, Prolink, is fused to the c-terminus of a GPCR,and β-arrestin is fused to the larger β-galactosidase fragment, EA(Enzyme Acceptor). Binding of β-arrestin to the activated GPCR causesthe complementation of the two enzyme fragments, forming an activeβ-galactosidase enzyme which can be measured using the chemiluminiescentPathHunter Flash Detection Kit (DiscoveRx, Fremont, Calif.: catalog#93-0001).

The Assay:

The stable CHO-K1 cells expressing CB₂-Prolink fusion protein wereplated over night in 384-well plates (Optiplate 384-Plus, PerkinElmer,Fremont Calif.; catalog #6007299) at 5000 cells/5 μL/well in theOpti-MEM medium (Invitrogen, Carlsbad, Calif.; catalog #31985088) with1% FBS. 5 uL of test compound diluted in Opti-MEM supplemented with 1%BSA was transferred to each well of the Optiplate. The plates were thenincubated at 37° C./5% CO₂ for two hours. 12 μL of substrate preparedfrom the PathHunter Flash Detection Kit (DiscoveRx, Fremont, Calif.:catalog #93-0001) was transferred to each well of the Optiplate. Theplate was then incubated in the dark at room temperature for 2 h, afterwhich the assay plate was read.

Assay Readout:

β-Arrestin assay readout was accomplished using a PHERAstar (BMG LabtechInc., Durham, N.C.) or an EnVision™ (PerkinElmer, Fremont Calif.)microplate reader.

B: CB₁ Assay

Compounds were screened for agonists of the human CB₁ receptor using theDiscoveRx PathHunter β-arrestin assay which measures the β-arrestinbinding to the CB₁ receptor upon its activation. CB₁ was cloned into thepCMV-PK vector (DiscoveRx, Fremont, Calif.; catalog #93-0167) andtransfected into the CHO-K1 EA-Arrestin parental cell line (DiscoveRx,Fremont, Calif.; catalog #93-0164). CHO-K1 positive clones stablyexpressing the CB₁-ProLink fusion protein were identified by theirresponses to the CB₁ agonist CP55,940. Clone #3 was chosen for its bigagonist window and homogenous expression as detected by anti-HA flowcytometry

Principle of the Assay:

The PathHunter β-arrestin assay measures the interaction of β-arrestinwith activated GPCRs using Enzyme Fragment Complementation (Yan et al.,J. Biomol. Screen. 7: 451-459, 2002). A small, 42 amino acidβ-galactosidase fragment, Prolink, is fused to the c-terminus of a GPCR,and β-arrestin is fused to the larger β-galactosidase fragment, EA(Enzyme Acceptor). Binding of β-arrestin to the activated GPCR causesthe complementation of the two enzyme fragments, forming an activeβ-galactosidase enzyme which can be measured using the chemiluminiescentPathHunter Flash Detection Kit (DiscoveRx, Fremont, Calif.: catalog#93-0001).

The Assay:

The stable CHO-K1 cells expressing CB₁-Prolink fusion protein wereplated over night in 384-well plates (Optiplate 384-Plus, PerkinElmer,Fremont Calif.; catalog #6007299) at 5000 cells/5 μL/well in theOpti-MEM medium (Invitrogen, Carlsbad, Calif.; catalog #31985088) with1% FBS. 5 uL of test compound diluted in Opti-MEM supplemented with 1%BSA was transferred to each well of the Optiplate. The plates were thenincubated at 37° C./5% CO₂ for two h. 12 μL of substrate prepared fromthe PathHunter Flash Detection Kit (DiscoveRx, Fremont, Calif.: catalog#93-0001) was transferred to each well of the Optiplate. The plate wasthen incubated in the dark at room temperature for 2 h, after which theassay plate was read.

Assay Readout:

β-Arrestin assay readout was accomplished using a PHERAstar (BMG LABTECHInc., Durham, N.C.) or EnVision™ (PerkinElmer, Fremont Calif.)microplate reader.

Certain compounds described herein had hCB₁ EC₅₀ values ranging fromabout 2.6 nM to about 89.06 μM in this assay and hCB₂ EC₅₀ valuesranging from about 643 pM to about 7 μM in this assay. Certain othercompounds described herein had hCB₁ EC₅₀ values ranging from about 10.9nM to about 100 μM in this assay and hCB₂ EC₅₀ values ranging from about384 pM to about 100 μM in this assay.

Each of Compounds 151, 174, 309, 515, 593, 625, 642, 644, 646, 667, 683,684, 690, 696, 698, 699, 700, 703, 704, 722, 746, 764, 765,766, 767,820, 821, 828, 841, 848, 889, 891, 896, 897, 902, 904, 912, 913, 918,919, 920, 921, 924, 926, 927, 930, and 931 had an hCB₂ EC₅₀ valueranging from about 0.72 nM to about 3 μM. Compounds 264, 493, and 844were not tested in this assay.

Certain compounds described herein and their corresponding hCB₂EC₅₀values are shown below.

Cmpd No. EC₅₀ 699 5.4 nM 764 5.9 nM 765 1.1 nM 919 2.8 nM 921 2.2 nM 9264.1 nM

Example 4 Radioligand Binding Assay

Preparation of Membranes:

HEK293 cells stably expressing human CB₂ receptor were collected, washedin ice cold PBS, and centrifuged at 48,000×g for 20 min at 4° C. Thecell pellet was then collected, resuspended in wash buffer (20 mM HEPES,pH 7.4 and 1 mM EDTA), homogenized on ice using a Brinkman Polytron, andcentrifuged at 48,000×g for 20 min at 4° C. The resultant pellet wasresuspended in ice cold 20 mM HEPES, pH 7.4, homogenized again on ice,recentrifuged for 20 min at 4° C., and membrane pellets were then storedat −80° C. until needed.

[³H]CP55,940 and [³H]WIN55,212-2 Radioligand Binding Assays:

Radioligand binding assays for human CB₂ receptors were performed usingtwo different agonist radioligands, [³H]CP55,940 and [³H]WIN55,212-2 andsimilar assay conditions. For both assays, nonspecific binding wasdetermined in the presence of 10 μM unlabeled compound. Competitionexperiments consisted of addition of 20 μL of assay buffer (50 mM Tris,pH 7.4, 2.5 mM EDTA, 5 mM MgCl₂, and 0.5 mg/mL of fatty acid free BSA)containing test compound (concentrations ranging from 1 pM to 100 μM),25 μL of radioligand (1 nM final assay concentration for [³H]CP55,904and [³H]WIN55,212-2), and 50 μL of membranes (20 μg/mL final protein forboth assays). Incubations were conducted for 1 h at room temperature,assay plates were filtered under reduced pressure over GF/B filters,washed with assay buffer and dried overnight in a 50° C. oven. Then, 25μL of BetaScint scintillation cocktail was added to each well, andplates were read in a Packard TopCount scintillation counter.

Certain compounds described herein had hCB₁ K_(i) values ranging fromabout 124 nM to about 19.36 μM in this assay and hCB₂ K_(i) valuesranging from about 3.22 nM to about 4.69 μM in this assay.

Example 5 Effect of Compounds on Osteoarthritis Pain

Injection of monosodium iodoacetate (MIA) into a joint (Kalbhen, 1987)inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase inchondrocytes, resulting in disruption of glycolysis and eventually incell death. The progressive loss of chondrocytes results in histologicaland morphological changes of the articular cartilage, closely resemblingthose seen in osteoarthritis patients.

The osteoarthritis was induced in 200 g male Sprague Dawley rats. Afterbrief anaesthesia by isoflurane rats received a single intra-articularinjection of MIA (2 mg) (Sigma Aldrich, Saint Louis, Mo., USA; Cat#19148) dissolved in 0.9% sterile saline in a 50 μL volume administeredthrough the patella ligament into the joint space of the left knee witha 30G needle. Following the injection, animals were allowed to recoverfrom anaesthesia before being returned to the main housing vivarium.

Typically during disease progression, there was an inflammation periodof 0-7 days post-intra-articular injection followed by progressivedegeneration of the cartilage and subchondral bone from days 14-55.Efficacy studies with a compound described herein for pain developmenttook place from day 14 onwards and were performed twice a week with atleast 3 days' wash-out in between each assay. Three different assayswere used to measure pain. Tactile allodynia was measured via von Freyassay, hind limb paw weight distribution was monitored using anincapacitence tester (Columbus Instruments, Columbus, Ohio, USA) andhind limb grip strength was measured using a grip strength meter(Columbus Instruments, Columbus, Ohio, USA). Briefly, the von Frey assaywas performed using the standard up down method with von-Frey filaments.Hind paw weight distribution was determined by placing rats in a chamberso that each hind paw rests on a separate force plate of theincapacitence tester. The force exerted by each hind limb (measured ingrams) is averaged over a 3 second period. Three measurements were takenfor each rat, and the change in hind paw weight distribution calculated.Peak hind limb grip force was conducted by recoding the maximumcompressive force exerted on the hind limb mesh gauge set on the gripstrength meter. During the testing, each rat was restrained and the pawof the injected knee was allowed to grip the mesh. The animal was thenpulled in an upward motion until their grip was broken. Each rat istested 3 times, with the contralateral paw used as a control.

Animals were base-lined prior to treatment of the test compound. The MIAtreated groups of rats (6 per group) were then dosed with either vehicle(PEG400, orally), Compound 493 (at 3 mg/kg, 10 mg/kg, and 30 mg/kg,orally) or with morphine (3 mg/kg, subcutaneously). Dosing volume was500 μL. One hour after dosing, von Frey assay, hind limb weightdistribution and/or hind limb grip analysis was performed to measure theefficacy of the test compound. Increase in paw withdrawal threshold(PWT) by Compound 493 in comparison with vehicle shown in FIG. 2 wasindicative of the test compound exhibiting therapeutic efficacy in theMIA model of osteoarthritis.

Example 6 Effects of Compounds on Skin-Incision Model in Rats

Postoperative pain was produced by a 1 cm incision of the skin andmuscle of the plantar surface of the rat hind paw as described (Brennanet al., 1996), with minor modifications. For surgery, rats weighing 200to 300 g were anesthetized with 2% isoflurane. The plantar surface ofthe right hind paw was prepared in a sterile manner with a 10%povidone-iodine solution. A 1 cm longitudinal incision was made with anumber 11 blade, through skin and fascia of the plantar aspect of thefoot, starting in the middle of the paw and extending toward the heel.The plantaris muscle was elevated and incised longitudinally. Afterhemostasis with gentle pressure, the skin was apposed with 2 mattresssutures of 5-0 nylon. The animals were allowed to recover individuallyin their cages with clean bedding.

Two to three hours after surgery, animals were treated with the testcompound. Compound 493 were dosed orally at 30 mg/kg. Tactile allodyniawas assessed with von Frey hair calibrated to bend at specific weights(0.4, 1, 2, 4, 6, 8, 15 g for animal weighing less than 250 g; 1, 2, 4,6, 8, 15, 26 g for animal weighing 250 g or more in some experiments).Regions adjacent to incision on the mid-plantar surface were firstprobed to assess the responsive spots with a von Frey force of 8 g. Ifthere was no withdrawal response, the next higher force (15 g) was useduntil no response at the highest force (26 g for rats weighing 250 g orhigher, 15 g for rats weighing less than 250 grams). Once responsivespot was identified, the 50% withdrawal threshold was then determinedusing the up/down method (Chaplan et al., 1994). Each trial started witha von Frey force of 2 g, if there was no withdrawal response, the nexthigher force was delivered. If there was a response, the next lowerforce was delivered. This procedure was performed until no response wasmade at the highest force (15 g or 26 g depending on animal size) oruntil four stimuli were delivered following the initial response. The50% paw withdrawal threshold (PWT) was then calculated as described inChaplan et al., 1994 (Chaplan S. R., Bach F. W., Pogrel J. W., Chung J.M., Yaksh T. L.: Quantitative assessment of tactile allodynia in the tatpaw. J. Neuroscience Methods 1994, 531(1):1022-1027). FIG. 4 shows thepain response of the animals treated with Compound 493 (dosed orally at30 mg/kg) compared with vehicle and indomethicin (dosed at 30 mg/kg).

Example 7 Effect of Compounds on FCA-Induced Hyperalgesia in Rats

Animal Info:

Male Sprague Dawley rats from Harlan (200-225 g when received) wereused. Upon arrival, rats were housed 4 per cage in shoe-boxpolycarbonate cages with wire tops, wood chip bedding and suspended foodand water bottles. Animals were acclimated for 5-7 days prior to beinginjected with Freund's complete adjuvant (FCA) (Sigma; catalog #5881).

Experimental Procedure:

2 days (48 h) before testing compounds, baseline readings of all ratswere taken right before FCA injection. Rats were then injected with 50μL FCA containing 1 mg/mL Mtb (Mycobacterium tuberculosis) in right hindfootpad under inhalation anesthesia (isoflurane). 48 hours after FCAinjection, readings were taken as pre-dosing baseline and then rats weredosed orally with 0.5 mL of vehicle or compound (0.5 mL per 250 g rat).Readings were taken again at 1 h post dosing. All readings were takenwith an Analgesy-Meter (Ugo Basile) which measures mechanicalhyperalgesia via paw pressure.

Clinical Scoring:

FCA-induced hyperalgesia was tested with an Analgesy-Meter. Briefly, theAnalgesy Meter applied an increasing pressure to the right hind paw. Thepaw withdrawal threshold was the pressure leading to withdrawal.

Drug Treatment:

48 hours after FCA injection, baseline readings were taken prior todosing of compounds, and then rats were dosed orally with vehicle(PEG400) or Compound 493 at 0.1, 1, 3, 10 and 30 mg/kg. Meanwhile agroup of rats were dosed orally with 50 mg/kg of Diclofenac as apositive control. Readings were taken again at 1 h post dosing. Dosingvolume was 500 μL per 250 g rat. As is apparent from FIG. 1, an increasein paw withdrawal threshold (PWT) for Compound 493 in comparison withthe vehicle indicates Compound 493 exhibited therapeutic efficacy in theFCA-induced hyperalgesia model of inflammatory pain at 1 h post dosing.

Example 8 Paclitaxel-Induced Allodynia in Sprague Dawley Rats

The mitotic inhibitor, paclitaxel (Taxol®) is one of the most effectiveand frequently used chemotherapeutic agents for the treatment of solidtumors as well as ovarian and breast cancers. Therapy however is oftenassociated with the unwanted side affects of painful peripheralneuropathy.

Animals:

Male Sprague Dawley rats [200-250 g](Harlan Laboratories Inc.,Livermore, Calif.) were housed three per cage and maintained in ahumidity-controlled (40-60%) and temperature-controlled (68-72° F.)facility on a 12 h: 12 h light/dark cycle (lights on at 6:30 am) withfree access to food (Harlan Teklad, Orange, Calif., Rodent Diet 8604)and water. Rats were allowed one week of habituation to the animalfacility before starting treatment.

Induction of Allodynia:

Rats were treated intraperitoneally, with 2 mg/kg of paclitaxel (SigmaAldrich, Saint Louis, Mo.) in 10% Cremophor vehicle (500 μL) on days 0,2, 4, and 6.

Clinical Scoring:

Tactile allodynia was tested using von Frey filaments. Briefly, the vonFrey assay was performed using the standardized up down method with vonFrey filaments, that determine the tactile sensitivity of the paw. Byapplying the increasingly or decreasingly thicker filaments to the pawin a logarithmic scale of actual force, a linear scale of perceivedintensity is determined.

Drug Treatment:

Eight days after the start of paclitaxel dosing, a baseline measurement(von Frey assay) was performed prior to dosing of compounds. Thepaclitaxel treated groups of rats (6 per group) were dosed orally, withvehicle (PEG400) or 10 mg/kg Compound 493. As a positive control, ratswere dosed intraperitoneally with 100 mg/kg gabapentin in water. Thedosing volume for oral and peritoneal treatment was 500 μL. The von Freyassay was performed to measure the efficacy of the test compound 30, 60and 180 minutes after dosing. An increase in paw withdrawal threshold(PWT) by treatment with Compound 493 in comparison with vehicle andgabapentin was indicative of the test compound exhibiting therapeuticefficacy in paclitaxel model of cancer pain. The time course showsmaximum efficacy at 1 h post-dosing. See FIG. 3.

Example 9 Effects of Compounds on Body Temperature and LocomotorActivity in Rats

Animals: Male Sprague-Dawley rats (300-400 g) were housed three per cageand maintained in a humidity-controlled (30-70%) andtemperature-controlled (20-22° C.) facility on a 12 h: 12 h light/darkcycle (lights on at 7:00 am) with free access to food (Harlan-Teklad,Orange, Calif., Rodent Diet 8604) and water. Rats were allowed one weekof habituation to the animal facility before testing.

Measurement of Body Temperature and Locomotor Activity:

Body temperature was measured using a stainless steel rat temperatureprobe connected to a temperature display device (Physitemp TH-5). Theprobe was inserted rectally to a depth of 1 inch and the reading wasrecorded approximately 10 s after insertion, when the reading hadstabilized. Body temperature was measured immediately before (time 0)and 60 min post-administration of compounds. Locomotor activity wasmeasured using the Hamilton-Kinder Motor Monitor system, which detectedblockage of photocell beams in a standard rat cage and transfers thisdata to a computer. Motor activity was measured for 30 min startingimmediately after the second body temperature measurement, from 60 to 90min post-administration. Compounds were dosed orally in a volume of 2 to6 mL/kg, suspended or dissolved in 100% PEG 400.

Example 10 Effects of Compounds on Spinal Nerve Ligation Surgery

Rats receive nerve injury by tight ligation of L5 and L6 spinal nervesclose to the spine, before they join (along with L4) to form the sciaticnerve. For this surgery, animals are placed under general anesthesiausing continuous inhalation of isoflurane. Surgery is performed in adedicated surgery room, using sterile instruments, surgical gloves, andaseptic procedures to prevent clinical infections. The surgical site isshaved and disinfected with iodine solution and alcohol. Animals areobserved continuously for their level of anesthesia, testing for theanimal's reflex response to tail or paw pinch. A heating pad is used tomaintain body temperature both during the procedure and while theanimals are recovering from anesthesia. For this procedure, a skinincision is made over the lower back at the level of L4-L6, and themuscle, ligaments, and facet joints are cut away from the spine. Correctlocation is confirmed by identifying the pelvis and the L5 transverseprocess. The L5 transverse is carefully removed to expose the L4 and L5nerves. L5 is carefully hooked (with a pulled glass hook) withoutdamaging L4 and tightly ligated (6-0 silk suture). L6 is then locatedjust under the pelvic bone, hooked and ligated as well. The wound isdebrided and closed with internal sutures and external staples. Animalsare administered a post-surgery injection of lactated Ringer's solutionand returned to their home cages. They are carefully monitored untilcompletely recovered from anesthesia (defined as the ability to movewithout significant ataxia), typically less than 10 min. Any animal withloss of motor control of the affected hind paw (L4 motor damage) areeuthanized. Neuropathic animals are first tested 7-10 days post surgeryfor the beginning of tactile allodynia. The allodynia is seenapproximately 14 days post surgery and persists for 45-50 days postsurgery. During this time analgesic compounds are tested for theirability to reduce or eliminate this chronic pain symptom.

Example 11 Effects of Compounds on Chronic Constriction Injury Surgery

Nerve injury is induced by loose ligature of the sciatic nerve. For thissurgery, animals are placed under general anesthesia using continuousinhalation of isoflurane. Surgery is performed in a dedicated surgeryroom, using sterile instruments, surgical gloves, and aseptic proceduresto prevent clinical infections. The surgical site is shaved anddisinfected with iodine solution and alcohol. Animals are observedcontinuously for their level of anesthesia, testing for the animal'sreflex response to tail or paw pinch and closely monitoring the animal'sbreathing. A heating pad is used to maintain body temperature while theanimals are recovering from anesthesia. For this procedure, a skinincision is made over the femur and the muscle is bluntly dissected toexpose the sciatic nerve. Four loose ligatures (Chromic gut absorbablesuture) are placed around the nerve, and the wound is closed withinternal sutures and external staples. Animals are administered apost-surgery injection of lactated ringers solution and returned totheir home cages. They are carefully monitored until complete recoveryfrom anesthesia (defined as the ability to move without significantataxia), typically less than 10 min. Neuropathic animals are firsttested 7-15 days post surgery for tactile allodynia. During this timeperiod analgesic compounds are tested for their ability to reduce oreliminate these chronic pain symptoms.

Example 12 Streptozotocin-Induced Painful Diabetic Peripheral Neuropathy(PDPN) Model

Male Sprague-Dawley rats were injected intraperitoneally with 50 mg/kgof streptozotocin (STZ) in sodium citrate buffer. 10% sucrose water wasprovided ad libitum for the first 48 hours post-STZ followed by regulardrinking water. Rats were monitored once weekly for blood glucose levelsand body weights. Development of tactile allodynia over time wasanalyzed using Von Frey filaments and a 50% withdrawal threshold wasdetermined using Dixon's up-down procedure. The effect of CB2 agonistsCompound 699 and Compound 919 on pain threshold was evaluated indiabetic and allodynic rats by administering 10 mg/kg dose of eithercompound orally in 0.5% methylcellulose vehicle. Tactile allodynia wasevaluated at 1, 4 and 6 hours post-dosing. As shown in FIG. 13 and FIG.14, both Compound 699 and Compound 919 showed robust and sustainedanalgesic efficacy over 6 hours in this model.

Example 13 Evaluation of Combination of Compound 699 and Morphine inRelieving Osteoarthritis Pain

Monosodium iodoacetate-induced osteoarthritis rats were treated with 10mg/kg dose of Compound 699 as positive control. Sub-efficacious 1 mpk(mg per kg) doses of Compound 699 or morphine were administered eitheralone or in combination and allodynic pain response was evaluated aschange in paw withdrawal threshold (PWT) using Von Frey test one hourpost-dosing. Compound 699 was administered orally and morphine wasadministered intraperitoneally. As shown in FIG. 15, the increase in PWTby Compound 699 in combination with morphine was greater than that seenby adding the increase in PWT of each compound together.

1 mpk 1 mpk 10 mpk Compound 699 + vehicle morphine Compound 699 Compound699 morphine 1.13 4.25 6.66 15.00 15.00 4.25 8.44 5.56 6.58 15.00 0.445.57 11.69 11.69 15.00 2.00 5.44 5.54 7.80 15.00 2.38 4.72 7.80 15.0015.00 0.20 2.02 3.58 15.00 7.80

Example 14 Powder X-Ray Diffraction

Powder X-ray Diffraction (PXRD) data were collected on an X'Pert PRO MPDpowder diffractometer (PANalytical, Inc.) with a Cu source set at 45 kVand 40 mA, Cu(Kα) radiation and an X'Celerator detector. Samples wereadded to the sample holder and smoothed flat with a spatula and weighpaper. With the samples spinning, X-ray diffractograms were obtained bya 12-min scan over the 2-theta range 5-40°2θ. Diffraction data wereviewed and analyzed with the X'Pert Data Viewer Software, version 1.0aand X'Pert HighScore Software, version 1.0b.

Example 15 Differential Scanning Calorimetry

Differential scanning calorimetry (DSC) studies were conducted using aTA Instruments, Q2000 at a heating rate 10° C./min. The instruments werecalibrated for temperature and energy using the melting point andenthalpy of fusion of an indium standard. Thermal events (desolvation,melting, etc.) were evaluated using Universal Analysis 2000 software,version 4.1D, Build 4.1.0.16.

Example 16 Thermal Gravimetric Analysis

Thermogravimetric analyses (TGA) were conducted using a TA InstrumentsTGA Q500 or Q5000 at a heating rate 10° C./min. The instruments werecalibrated using a standard weight for the balance, and Alumel andNickel standards for the furnace (Curie point measurements). Thermalevents such as weight-loss are calculated using the Universal Analysis2000 software, version 4.1D, Build 4.1.0.16.

Example 17 Dynamic Moisture-Sorption Analysis

A dynamic moisture-sorption (DMS) study was conducted using a dynamicmoisture-sorption analyzer, VTI Corporation, SGA-100. The instrument wascalibrated using polyvinyl pyrrolidone (PVP) and NaCl. Samples wereprepared for DMS analysis by placing 5 mg to 20 mg of a sample in atared sample holder. The sample was placed on the hang-down wire of theVTI balance. A drying step was run, typically at 40° C. and 0.5-1% RHfor 1 h. The isotherm temperature is 25° C. Defined % RH holds typicallyranged from 10% RH to 90% RH, with intervals of 10 to 20% RH. A % weightchange smaller than 0.010% over 10 min, or up to 2 h, whichever occurredfirst, was required before continuing to the next % RH hold. The watercontent of the sample equilibrated as described above was determined ateach % RH hold.

The DMS profile (adsorption/desorption isotherm) for the anhydrouscrystalline form of Compound 699 is shown in FIG. 18. The correspondingdata in tabular form is provided below:

Elapsed Time Weight Weight Sample Sample (min) (mg) (% Change)Temperature RH (%) 46.6 9.6782 0 25.46 1.1 71.4 9.6928 0.151 25.32 29.9491.1 9.7055 0.282 25.31 49.86 111.2 9.7248 0.482 25.3 69.77 129.1 9.73440.581 25.29 79.70 160.1 9.7519 0.762 25.3 89.72 180.1 9.7291 0.526 25.3070.11 200.1 9.7134 0.364 25.3 50.07 218.6 9.6957 0.181 25.29 29.99 234.49.6859 0.080 25.29 10.06

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention.

The invention claimed is:
 1. A composition comprising a compoundselected from compounds of Formula Ia and pharmaceutically acceptablesalts, solvates, hydrates, and N-oxides thereof:

wherein: R¹, R², R³, R⁴, R⁵, and R⁶ are each independently selectedfrom: H and C₁-C₆ alkyl; X is NR⁷ and Y is CC(O)N(R⁸)R⁹; or X isCC(O)N(R⁸)R⁹ and Y is NR⁷; R⁷ is —R¹⁰—R¹¹—R¹²—R¹³; wherein: R¹⁰ isabsent; R¹¹ is absent; R¹² is absent; and R¹³ is selected from: C₁-C₆alkyl, aryl, C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl;wherein said C₁-C₆ alkyl, aryl, and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, amino, C₃-C₇cycloalkyl, cyano, C₂-C₈ dialkylamino, C₁-C₆ haloalkyl, halogen, andhydroxyl; R⁸ is —R¹⁴—R¹⁵—R¹⁶—R¹⁷; wherein: R¹⁴ is selected from: C₁-C₆alkylene, C₃-C₇ cycloalkenylene, C₃-C₇ cycloalkylene, heteroarylene, andheterocyclylene; wherein said C₁-C₆ alkylene and heterocyclylene areeach optionally substituted with one or more substituents selected from:C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, carboxy,heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆ alkyl andaryl are optionally substituted with one substituent selected from:C₁-C₆ alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R¹⁴ is absent;R¹⁵ is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C₁-C₆ alkylene, C₃-C₇cycloalkylene, heteroarylene, and heterocyclylene; wherein saidheterocyclylene is optionally substituted with C₁-C₆ alkyl; or R¹⁵ isabsent; R¹⁶ is C₁-C₆ alkylene; or R¹⁶ is absent; and R¹⁷ is selectedfrom: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino, aryl, arylamino,arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano,C₃-C₇ cycloalkyl, C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈dialkylamino, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkyl, heteroaryl,heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy;wherein said C₁-C₆ alkylamino, amino, aryl, arylamino, aryloxy, C₅-C₁₁bicycloalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylamino, heteroaryl,heterobicyclyl, heterocyclyl, and ureyl are each optionally substitutedwith one or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, amino, aryl, carboxy,cyano, C₃-C₇ cycloalkyl, C₂-C₈ dialkylamino, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and R⁹ isselected from: H, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; or R⁸ and R⁹together with the nitrogen atom to which they are both bonded form agroup selected from: heterocyclyl and heterobicyclyl, each optionallysubstituted with one or more substituents selected from:Carbo-C₁-C₆-alkoxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, carbo-C₁-C₆-alkoxy,C₁-C₆ haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, andhydroxyl; wherein said aryl, C₁-C₆ alkyl, and heteroaryl are optionallysubstituted with one substituent selected from: C₃-C₇ cycloalkyl, C₁-C₆alkoxy, halogen, and hydroxyl, and one or more known pharmaceuticalagents selected from: analgesic agents and antidiabetic agents.
 2. Thecomposition according to claim 1, further comprising a pharmaceuticallyacceptable carrier.
 3. The composition according to claim 1, wherein thecompound is selected from compounds of Formula Ie and pharmaceuticallyacceptable salts, solvates, hydrates, and N-oxides thereof:

wherein: R⁷ is —R¹⁰—R¹¹—R¹²—R¹³; wherein: R¹⁰ is absent; R¹¹ is absent;R¹² is absent; and R¹³ is selected from: C₁-C₆ alkyl, aryl, C₃-C₇cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆alkyl, aryl, and heteroaryl are each optionally substituted with one ortwo substituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylamino, C₁-C₆ alkylsulfonyl, amino, C₃-C₇ cycloalkyl, cyano, C₂-C₈dialkylamino, C₁-C₆ haloalkyl, halogen, and hydroxyl; R⁸ is—R¹⁴—R¹⁵—R¹⁶—R¹⁷; wherein: R¹⁴ is selected from: C₁-C₆ alkylene, C₃-C₇cycloalkenylene, C₃-C₇ cycloalkylene, heteroarylene, andheterocyclylene; wherein said C₁-C₆ alkylene and heterocyclylene areeach optionally substituted with one or more substituents selected from:C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, carboxy,heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆ alkyl andaryl are optionally substituted with one substituent selected from:C₁-C₆ alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R¹⁴ is absent;R¹⁵ is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C₁-C₆ alkylene, C₃-C₇cycloalkylene, heteroarylene, and heterocyclylene; wherein saidheterocyclylene is optionally substituted with C₁-C₆ alkyl; or R¹⁵ isabsent; R¹⁶ is C₁-C₆ alkylene; or R¹⁶ is absent; and R¹⁷ is selectedfrom: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino, aryl, arylamino,arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano,C₃-C₇ cycloalkyl, C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈dialkylamino, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkyl, heteroaryl,heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy;wherein said C₁-C₆ alkylamino, amino, aryl, arylamino, aryloxy, C₅-C₁₁bicycloalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylamino, heteroaryl,heterobicyclyl, heterocyclyl, and ureyl are each optionally substitutedwith one or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, amino, aryl, carboxy,cyano, C₃-C₇ cycloalkyl, C₂-C₈ dialkylamino, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and R⁹ isselected from: H, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; or R⁸ and R⁹together with the nitrogen atom to which they are both bonded form agroup selected from: heterocyclyl and heterobicyclyl, each optionallysubstituted with one or more substituents selected from:Carbo-C₁-C₆-alkoxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, carbo-C₁-C₆-alkoxy,C₁-C₆ haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, andhydroxyl; wherein said aryl, C₁-C₆ alkyl, and heteroaryl are optionallysubstituted with one substituent selected from: C₃-C₇ cycloalkyl, C₁-C₆alkoxy, halogen, and hydroxyl.
 4. The composition according to claim 1,wherein the compound is selected from the following compounds andpharmaceutically acceptable salts, solvates, and hydrates thereof:Compound 151:(1aR,5aR)-2-(5-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-amide; Compound 174:(1aR,5aR)-2-(2,4-Dichloro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (1-hydroxymethyl-cyclopropyl)-amide; Compound 264:(1aR,5aR)-2-(5-Cyano-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-amide; Compound 309:(1aR,5aR)-2-(5-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-amide; Compound 493:(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-amide; Compound 515:1-(2,4-Difluoro-phenyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-amide; Compound 593:(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid tert-butylamide; Compound 625:(1aR,5aR)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (cyano-dimethyl-methyl)-amide; Compound 642:(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide; Compound 644:(1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-amide; Compound 646: Phosphoric acidmono-(2-{[(1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-2-methyl-propyl)ester; Compound 667:(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid [2,2-dimethyl-1-((S)-methylcarbamoyl)-propyl]-amide; Compound 683:Phosphoric acidmono-{(S)-3,3-dimethyl-2-[((1aR,5aR)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl)-amino]-butyl}ester; Compound 684:(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-2-hydroxy-1-tetrahydro-pyran-4-yl-ethyl)-amide; Compound 690:(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2-methyl-propyl)-amide; Compound 696:(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide; Compound 698:(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (1-hydroxymethyl-cyclobutyl)-amide; Compound 699:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide; Compound 700:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (1-pyridin-2-yl-cyclobutyl)-amide; Compound 703: Phosphoric acidmono-((S)-3,3-dimethyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl)ester; Compound 704:(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide; Compound 722:(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-methylcarbamoyl-phenyl-methyl)-amide; Compound 746:(S)-3,3-Dimethyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyricacid methyl ester; Compound 764:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (1-trifluoromethyl-cyclopropyl)-amide; Compound 765:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (1-trifluoromethyl-cyclobutyl)-amide; Compound 766:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((R)-2,2-dimethyl-1-pyridin-2-yl-propyl)-amide; Compound 767:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-2,2-dimethyl-1-pyridin-2-yl-propyl)-amide; Compound 820:(1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide; Compound 821:(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (1-methyl-cyclobutyl)-amide; Compound 828:(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((R)-1,2-dimethyl-propyl)-amide; Compound 841:(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid [(S)-2-hydroxy-1-(tetrahydro-pyran-4-yl)-ethyl]-amide; Compound844: (1aR,5aR)-Pentanedioic acidmono-((S)-3-methyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl)ester; Compound 848: (1aS,5aS)-(S)-2-Amino-3-methyl-butyric acid(S)-3,3-dimethyl-2-{[2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butylester; Compound 889:(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl)-amide; Compound891:(1aS,5aS)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-3,3,3-trifluoro-1-hydroxymethyl-propyl)-amide; Compound 896:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2-methyl-propyl)-amide; Compound 897:(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-fluoro-1,1-dimethyl-ethyl)-amide; Compound 902:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid N′-tert-butyl-hydrazide; Compound 904:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2-fluoro-1,1-dimethyl-ethyl)-amide; Compound 912:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((R)-1,2-dimethyl-propyl)-amide; Compound 913:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-2-hydroxy-1-phenyl-ethyl)-amide; Compound 918:(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-fluoromethyl-2,2-dimethyl-propyl)-amide; Compound 919:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide; Compound 920:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((1S,2S)-2-hydroxy-indan-1-yl)-amide; Compound 921:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((1S,2R)-2-hydroxy-indan-1-yl)-amide; Compound 924:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (1-fluoromethyl-cyclobutyl)-amide; Compound 926:(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (1-trifluoromethyl-cyclobutyl)-amide; Compound 927:(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide; Compound 930:(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid (1-trifluoromethyl-cyclopropyl)-amide; and Compound 931:(1aR,5aR)-2-(4-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide.
 5. The composition according toclaim 1, wherein the compound is selected from the following compoundand pharmaceutically acceptable salts, solvates, and hydrates thereof:Compound 696:(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.
 6. The compositionaccording to claim 1, wherein the compound is selected from thefollowing compound and pharmaceutically acceptable salts, solvates, andhydrates thereof: Compound 699:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.
 7. The compositionaccording to claim 1, wherein the compound is an anhydrous crystallineform of: Compound 699:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.
 8. The compositionaccording to claim 1, wherein the analgesic agent is chosen from:non-opioid drugs, opioid drugs, and co-analgesic medications.
 9. Thecomposition according to claim 8, wherein the non-opioid drug is chosenfrom: non steroidal anti-inflammatory agents, choline magnesiumtrisalicylate, sulfasalazine, olsalazin, phenacetin, tenoxicam,phenylbutazone, oxyphenthartazone, tapentadol, celecoxib, etoricoxib,lumiracoxib, rofecoxib, parecoxib, and ziconotide.
 10. The compositionaccording to claim 9, wherein the non steroidal anti-inflammatory agentis chosen from: acemetacin, acetaminophen, aminoprofen, aspirin,benoxaprofen, bucloxic acid, carprofen, choline magnesium salicylate,choline salicylate, clidanac, diclofenac, diflunisal, diflurisal,etodolac, fenoprofen, fenoprofen calcium, fentiazac, flosulide,flubufen, flufenamic acid, flufenisal, flurbiprofen, fluprofen,ibuprofen, indoprofen, indomethacin, isoxicam, ketoprofen, ketorolactromethamine, lornoxicam, magnesium salicylate, meclofenamic acid,meclofenamate sodium, mefenamic acid, meloxicam, muroprofen, nabumetone,naproxen, nepafenac, niflumic acid, nimesulide, oxaprozin, oxpinac,piroprofen, piroxicam, pramoprofen, ramifenazone, salsalate,salicylsalicylic acid, sodium salicylate, sudoxicam, sulindac, suprofen,tiaprofenic acid, tiopinac, tolfenamic acid, tolmetin, trioxaprofen,zidometacin, and zomepirac.
 11. The composition according to claim 8,wherein the opioid drug is chosen from: alfentanil, allylprodine,alphaprodine, anileridine, apomorphine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone,dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine,dilaudid, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, fentanyl, heroin, hydrocodeine, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, 6-monoacetylmorphine,morphine, morphine-6-glucuronide, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, noscapine, opium, oxycodone, oxymorphone, papavereturn,papverine, pentazocine, pethidine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, andtramadol.
 12. The composition according to claim 1, wherein theanalgesic agent comprises an NSAID and an opioid drug.
 13. Thecomposition according to claim 1, wherein the analgesic agent is chosenfrom: vicodin, percocet, norco, lorcet, darvocet, and percodan.
 14. Amethod for preparing a composition comprising the step of admixing acompound selected from compounds of Formula Ia and pharmaceuticallyacceptable salts, solvates, hydrates, and N-oxides thereof:

wherein: R¹, R², R³, R⁴, R⁵, and R⁶ are each independently selectedfrom: H and C₁-C₆ alkyl; X is NR⁷ and Y is CC(O)N(R⁸)R⁹; or X isCC(O)N(R⁸)R⁹ and Y is NR⁷; R⁷ is —R¹⁰—R¹¹—R¹²—R¹³; wherein: R¹⁰ isabsent; R¹¹ is absent; R¹² is absent; and R¹³ is selected from: C₁-C₆alkyl, aryl, C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl;wherein said C₁-C₆ alkyl, aryl, and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, amino, C₃-C₇cycloalkyl, cyano, C₂-C₈ dialkylamino, C₁-C₆ haloalkyl, halogen, andhydroxyl; R⁸ is —R¹⁴—R¹⁵—R¹⁶—R¹⁷; wherein: R¹⁴ is selected from: C₁-C₆alkylene, C₃-C₇ cycloalkenylene, C₃-C₇ cycloalkylene, heteroarylene, andheterocyclylene; wherein said C₁-C₆ alkylene and heterocyclylene areeach optionally substituted with one or more substituents selected from:C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, carboxy,heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆ alkyl andaryl are optionally substituted with one substituent selected from:C₁-C₆ alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R¹⁴ is absent;R¹⁵ is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C₁-C₆ alkylene, C₃-C₇cycloalkylene, heteroarylene, and heterocyclylene; wherein saidheterocyclylene is optionally substituted with C₁-C₆ alkyl; or R¹⁵ isabsent; R¹⁶ is C₁-C₆ alkylene; or R¹⁶ is absent; and R¹⁷ is selectedfrom: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino, aryl, arylamino,arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano,C₃-C₇ cycloalkyl, C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈dialkylamino, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkyl, heteroaryl,heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy;wherein said C₁-C₆ alkylamino, amino, aryl, arylamino, aryloxy, C₅-C₁₁bicycloalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylamino, heteroaryl,heterobicyclyl, heterocyclyl, and ureyl are each optionally substitutedwith one or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, amino, aryl, carboxy,cyano, C₃-C₇ cycloalkyl, C₂-C₈ dialkylamino, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and R⁹ isselected from: H, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; or R⁸ and R⁹together with the nitrogen atom to which they are both bonded form agroup selected from: heterocyclyl and heterobicyclyl, each optionallysubstituted with one or more substituents selected from:Carbo-C₁-C₆-alkoxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, carbo-C₁-C₆-alkoxy,C₁-C₆ haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, andhydroxyl; wherein said aryl, C₁-C₆ alkyl, and heteroaryl are optionallysubstituted with one substituent selected from: C₃-C₇ cycloalkyl, C₁-C₆alkoxy, halogen, and hydroxyl, and one or more known pharmaceuticalagents selected from: analgesic agents and antidiabetic agents.
 15. Apharmaceutical product selected from: a pharmaceutical composition, aformulation, a dosage form, a combined preparation, a twin pack, and akit; comprising a compound selected from compounds of Formula Ia andpharmaceutically acceptable salts, solvates, hydrates, and N-oxidesthereof:

wherein: R¹, R², R³, R⁴, R⁵, and R⁶ are each independently selectedfrom: H and C₁-C₆ alkyl; X is NR⁷ and Y is CC(O)N(R⁸)R⁹; or X isCC(O)N(R⁸)R⁹ and Y is NR⁷; R⁷ is —R¹⁰—R¹¹—R¹²—R¹³; wherein: R¹⁰ isabsent; R¹¹ is absent; R¹² is is absent; and R¹³ is selected from: C₁-C₆alkyl, aryl, C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl;wherein said C₁-C₆ alkyl, aryl, and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, amino, C₃-C₇cycloalkyl, cyano, C₂-C₈ dialkylamino, C₁-C₆ haloalkyl, halogen, andhydroxyl; R⁸ is —R¹⁴—R¹⁵—R¹⁶—R¹⁷; wherein: R¹⁴ is selected from: C₁-C₆alkylene, C₃-C₇ cycloalkenylene, C₃-C₇ cycloalkylene, heteroarylene, andheterocyclylene; wherein said C₁-C₆ alkylene and heterocyclylene areeach optionally substituted with one or more substituents selected from:C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, carboxy,heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆ alkyl andaryl are optionally substituted with one substituent selected from:C₁-C₆ alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R¹⁴ is absent;R¹⁵ is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C₁-C₆ alkylene, C₃-C₇cycloalkylene, heteroarylene, and heterocyclylene; wherein saidheterocyclylene is optionally substituted with C₁-C₆ alkyl; or R¹⁵ isabsent; R¹⁶ is C₁-C₆ alkylene; or R¹⁶ is absent; and R¹⁷ is selectedfrom: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino, aryl, arylamino,arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano,C₃-C₇ cycloalkyl, C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈dialkylamino, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkyl, heteroaryl,heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy;wherein said C₁-C₆ alkylamino, amino, aryl, arylamino, aryloxy, C₅-C₁₁bicycloalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylamino, heteroaryl,heterobicyclyl, heterocyclyl, and ureyl are each optionally substitutedwith one or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, amino, aryl, carboxy,cyano, C₃-C₇ cycloalkyl, C₂-C₈ dialkylamino, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and R⁹ isselected from: H, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; or R⁸ and R⁹together with the nitrogen atom to which they are both bonded form agroup selected from: heterocyclyl and heterobicyclyl, each optionallysubstituted with one or more substituents selected from:Carbo-C₁-C₆-alkoxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, carbo-C₁-C₆-alkoxy,C₁-C₆ haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, andhydroxyl; wherein said aryl, C₁-C₆ alkyl, and heteroaryl are optionallysubstituted with one substituent selected from: C₃-C₇ cycloalkyl, C₁-C₆alkoxy, halogen, and hydroxyl, and one or more known pharmaceuticalagents selected from: analgesic agents and antidiabetic agents.
 16. Amethod for the treatment of pain in an individual in need thereof,comprising administering to said individual, a therapeutically effectiveamount of a compound selected from compounds of Formula Ia andpharmaceutically acceptable salts, solvates, hydrates, and N-oxidesthereof:

wherein: R¹, R², R³, R⁴, R⁵, and R⁶ are each independently selectedfrom: H and C₁-C₆ alkyl; X is NR⁷ and Y is CC(O)N(R⁸)R⁹; or X isCC(O)N(R⁸)R⁹ and Y is NR⁷; R⁷ is —R¹⁰—R¹¹—R¹²—R¹³; wherein: R¹⁰ isabsent; R¹¹ is absent; R¹² is absent; and R¹³ is selected from: C₁-C₆alkyl, aryl, C₃-C₇ cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl;wherein said C₁-C₆ alkyl, aryl, and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, amino, C₃-C₇cycloalkyl, cyano, C₂-C₈ dialkylamino, C₁-C₆ haloalkyl, halogen, andhydroxyl; R⁸ is —R¹⁴—R¹⁵—R¹⁶—R¹⁷; wherein: R¹⁴ is selected from: C₁-C₆alkylene, C₃-C₇ cycloalkenylene, C₃-C₇ cycloalkylene, heteroarylene, andheterocyclylene; wherein said C₁-C₆ alkylene and heterocyclylene areeach optionally substituted with one or more substituents selected from:C₁-C₆ alkoxycarbonyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, carboxy,heteroaryl, heterocyclyl, and hydroxyl; wherein said C₁-C₆ alkyl andaryl are optionally substituted with one substituent selected from:C₁-C₆ alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R¹⁴ is absent;R¹⁵ is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C₁-C₆ alkylene, C₃-C₇cycloalkylene, heteroarylene, and heterocyclylene; wherein saidheterocyclylene is optionally substituted with C₁-C₆ alkyl; or R¹⁵ isabsent; R¹⁶ is C₁-C₆ alkylene; or R¹⁶ is absent; and R¹⁷ is selectedfrom: H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylcarboxamide, C₂-C₆ alkynyl, ureyl, amino, aryl, arylamino,arylcarbonyl, aryloxy, carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano,C₃-C₇ cycloalkyl, C₅-C₁₁ bicycloalkyl, C₃-C₇ cycloalkylamino, C₂-C₈dialkylamino, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkyl, heteroaryl,heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy;wherein said C₁-C₆ alkylamino, amino, aryl, arylamino, aryloxy, C₅-C₁₁bicycloalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylamino, heteroaryl,heterobicyclyl, heterocyclyl, and ureyl are each optionally substitutedwith one or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, amino, aryl, carboxy,cyano, C₃-C₇ cycloalkyl, C₂-C₈ dialkylamino, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and R⁹ isselected from: H, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; or R⁸ and R⁹together with the nitrogen atom to which they are both bonded form agroup selected from: heterocyclyl and heterobicyclyl, each optionallysubstituted with one or more substituents selected from:Carbo-C₁-C₆-alkoxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, carbo-C₁-C₆-alkoxy,C₁-C₆ haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, andhydroxyl; wherein said aryl, C₁-C₆ alkyl, and heteroaryl are optionallysubstituted with one substituent selected from: C₃-C₇ cycloalkyl, C₁-C₆alkoxy, halogen, and hydroxyl, and one or more known pharmaceuticalagents selected from: analgesic agents, antidiabetic agents,osteoarthritis agents, and anticancer agents.
 17. The method accordingto claim 16, wherein the pain is chosen from: bone and joint pain, painassociated with osteoarthritis, hyperalgesia, allodynia, inflammatorypain, inflammatory hyperalgesia, neuropathic pain, neuropathichyperalgesia, acute nociception, muscle pain, dental pain, migraine andother headache pain, pain that occurs as an adverse effect oftherapeutics in an individual, and pain associated with a disorderselected from: cancer, multiple sclerosis, allergic reactions, nephriticsyndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia,HIV related-neuropathy, sciatica, and autoimmune conditions.
 18. Themethod according to claim 16, wherein the compound is selected from thefollowing compound and pharmaceutically acceptable salts, solvates, andhydrates thereof: Compound 696:(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.
 19. The methodaccording to claim 16, wherein the compound is selected from thefollowing compound and pharmaceutically acceptable salts, solvates, andhydrates thereof: Compound 699:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.
 20. The methodaccording to claim 16, wherein the compound is an anhydrous crystallineform of: Compound 699:(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylicacid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.